PHYSIOLOGICAL REVIEWS Vol. 79, No. 1, January 1999 Printed in U.S.A. Regulation of the Hypothalamic-Pituitary-Adrenal Axis by Cytokines: Actions and Mechanisms of Action ANDREW V. TURNBULL AND CATHERINE L. RIVIER The Clayton Foundation Laboratories for Peptide Biology, The Salk Institute, La Jolla, California; and North Western Injury Research Centre, University of Manchester, Manchester, United Kingdom 2 2 2 5 8 10 10 12 13 13 14 16 17 18 18 Downloaded from on April 23, 2014 I. Introduction A. Hormones and cytokines: definitions B. Concept of bidirectional communication between immune and neuroendocrine systems: a historical perspective C. Cytokines D. Hypothalamic-pituitary-adrenal axis II. Cytokine Influence on Hypothalamic-Pituitary-Adrenal Axis Secretory Activity In Vivo A. Animal studies B. Human studies III. Physiological/Pathophysiological Circumstances in Which Endogenous Cytokines Play a Role in Regulation of Hypothalamic-Pituitary-Adrenal Axis A. Viral disease B. Endotoxin treatment C. Local inflammation D. Physical and psychological stress E. Basal hypothalamic-pituitary-adrenal activity IV. Cytokine Actions on the Central Nervous System, Pituitary, and Adrenal A. Evidence that cytokines activate the hypothalamic-pituitary-adrenal axis primarily at the level of the central nervous system B. Evidence for direct effects of cytokines on pituitary adrenocorticotropic hormone secretion C. Evidence for direct actions of cytokines on adrenal glucocorticoid secretion V. Mechanisms of Hypothalamic-Pituitary-Adrenal Axis Activation by Interleukin-1 A. Direct actions on pituitary and adrenal B. Penetration of cytokines into brain C. Role of readily diffusible intermediates D. Induction of intermediates at blood-brain barrier interface E. Actions at circumventricular organs F. Potential role of catecholamines and evidence of activation of medullary cell groups G. Activation of vagal afferent fibers H. Cytokine synthesis within brain I. Local interleukin-1 induction of circulating interleukin-6 VI. Conclusions 19 26 30 31 31 32 33 36 37 39 40 41 43 43 Turnbull, Andrew V., and Catherine L. Rivier. Regulation of the Hypothalamic-Pituitary-Adrenal Axis by Cytokines: Actions and Mechanisms of Action. Physiol. Rev. 79: 1–71, 1999.—Glucocorticoids are hormone products of the adrenal gland, which have long been recognized to have a profound impact on immunologic processes. The communication between immune and neuroendocrine systems is, however, bidirectional. The endocrine and immune systems share a common ‘‘chemical language,’’ with both systems possessing ligands and receptors of ‘‘classical’’ hormones and immunoregulatory mediators. Studies in the early to mid 1980s demonstrated that monocyte-derived or recombinant interleukin-1 (IL-1) causes secretion of hormones of the hypothalamic-pituitary-adrenal (HPA) axis, establishing that immunoregulators, known as cytokines, play a pivotal role in this bidirectional communication between the immune and neuroendocrine systems. The subsequent 10–15 years have witnessed demonstrations that numerous members of several cytokine families increase the secretory activity of the HPA axis. Because this neuroendocrine action of cytokines is mediated primarily at the level of the central nervous system, studies investigating the mechanisms of HPA activation produced by cytokines take on a more broad significance, with findings relevant to the more fundamental question of how cytokines signal the brain. This article reviews published findings that have documented which cytokines have been shown to influence hormone secretion from the HPA axis, 0031-9333/99 $15.00 Copyright q 1999 the American Physiological Society / 9j0c$$oc11 P13-8 11-25-98 11:16:36 1 pra APS-Phys Rev 2 ANDREW V. TURNBULL AND CATHERINE L. RIVIER Volume 79 determined under what physiological/pathophysiological circumstances endogenous cytokines regulate HPA axis activity, established the possible sites of cytokine action on HPA axis hormone secretion, and identified the potential neuroanatomic and pharmacological mechanisms by which cytokines signal the neuroendocrine hypothalamus. I. INTRODUCTION A. Hormones and Cytokines: Definitions / 9j0c$$oc11 P13-8 B. Concept of Bidirectional Communication Between Immune and Neuroendocrine Systems: a Historical Perspective Regulation of the immune system by the adrenal gland was observed as early as the middle of the 19th century when Thomas Addison (3) documented that a patient with adrenal insufficiency had an excess of circulating lymphocytes. In agreement with this observation, removal of the adrenal gland of the rat was found to produce hypertrophy of the thymus (an organ responsible for the manufacture of mature lymphocytes) (363). Perhaps the best known of early experimental studies were those of Hans Selye (764, 765), who found that enlargement of the adrenal gland and involution of the thymus were communal features of an animal’s response to stress, regardless of the nature of the injurious insult. These early studies clearly suggested a close association between adrenal gland physiology and immune activity. The isolation of the active principal of the adrenal cortex, cortisone, by Kendall and Reichstein in the late 11-25-98 11:16:36 pra APS-Phys Rev Downloaded from on April 23, 2014 Defining what is meant by the term hormone, and what is meant by the term cytokine, is certainly no easy task. Indeed, the work reviewed in this article has changed many people’s opinion as to what our definitions of these classes of cell-cell signaling molecules should be. However, we are faced at the outset with conveying to the reader what ‘‘we’’ mean when we use the terms cytokines and hormones throughout this review. A classical endocrinology textbook definition of a hormone is ‘‘a biomolecule, which is produced by a specialized cell type, is secreted from a ductless gland directly into the bloodstream, and acts on distant target cells/tissues, to regulate pre-existing cellular activities.’’ Chemically, hormones are small to large polypeptides, proteins, glycoproteins, derivatives of aromatic amino acids, or steroids. In the case of the pituitary peptide hormone adrenocorticotropin (ACTH), it is produced by corticotropes (specialized cell type) within the anterior pituitary (a ductless gland), is secreted into the general circulation, and acts predominantly on the adrenal cortex (a distant target) to enhance glucocorticoid secretion. This is perhaps a narrow view of a hormone, because many ‘‘classical’’ hormones are also synthesized and act within the brain and are produced and act locally within the periphery. On the other hand, it is perhaps too broad, because under this definition CO2 produced by exercising muscle and stimulating respiration might have to be considered a hormone also. However, it is a fairly accurate description of what most people understand when thinking of a hormone acting in a ‘‘classical endocrine fashion.’’ In contrast to hormones that have most commonly been associated with the ‘‘endocrine system,’’ cytokines have been classically associated with the ‘‘immune system.’’ Defining a cytokine is even more difficult than defining a hormone. For the purposes of the work described within this review, we found the definition used in The Cytokine Handbook (862) most useful. Here cytokines are defined as ‘‘regulatory proteins secreted by white blood cells and a variety of other cells in the body; the pleiotropic actions of cytokines include numerous effects on cells of the immune system and modulation of inflammatory responses.’’ This definition is somewhat narrow in that it probably overemphasizes the importance of the immune system as a source and target, but probably reflects most accurately people’s first thoughts when they think of cyto- kines. It certainly reflects best the definition that would have been applied at the time when the majority of the work described in this article was performed. Under any definition, the term cytokine encompasses the ‘‘monokines’’ (monocyte/macrophage-derived mediators) and ‘‘lymphokines’’ (lymphocyte-derived mediators), which were terms commonly used in the earlier studies described in this review. Table 1 was compiled of what is presently known of the features of hormones and cytokines. Although this is again not definitive, it is fair to say that if the majority of characteristics of the substance under consideration fit in the cytokine column, then the substance is a cytokine, and if the majority of characteristics fit in the hormone column, then it is a hormone. It should be pointed out that the same chemical substance could be classified differently depending on the ‘‘setting’’ under consideration. For example, prolactin produced by the pituitary and acting on the mammary gland is clearly acting in an ‘‘endocrine hormone’’ fashion. However, prolactin can also be produced by, and act on, lymphocytes, a situation in which it might be better classified as a cytokine. Perhaps the key difference between cytokines and hormones that we indicate in Table 1 is that cytokines are regulators of predominantly local tissue processes, whereas hormones function as regulators predominantly of ‘‘systemic’’ or ‘‘whole body’’ homeostasis. January 1999 TABLE REGULATION OF HPA AXIS BY CYTOKINES 3 1. Features of cytokines and classical endocrine hormones Structure Cell sources Concentrations in healthy, stress-free subjects Location of action relative to secretion Range of activities ‘‘Redundancy’’ Cytokine Classical Endocrine Hormone Large polypeptides, proteins, or glycoproteins Secreted by white blood cells (and many other cells in numerous types of tissues and organs) Very low (virtually absent); increase markedly during tissue disease, injury, or repair Act predominantly locally, in a paracrine or autocrine manner ‘‘Pleiotropic,’’ multiple target cell types and broad spectrum of actions Small to large polypeptides, proteins, glycoproteins, derivatives of aromatic amino acids, or steroids Secreted by one type of specialized cell within a ductless gland (an ‘‘endocrine gland’’) Display great overlap of biological activities (i.e., ‘‘redundancy’’) Function predominantly as regulators of local tissue processes Function Usually measurable and commonly display pulsatile and circadian patterns of secretion Act on distant target cells Breadth of actions highly variable: many anterior pituitary hormones (e.g., TSH, ACTH) have highly limited actions, but ‘‘target gland’’ hormones (e.g., T3, T4, and glucocorticoids) have very broad range of activities Far less overlap of biological activities; deficiency in single hormone usually produces marked abnormalities Function predominantly as regulators of systemic or ‘‘whole body’’ homeostasis TSH, thyroid-stimulating hormone; ACTH, adrenocorticotropin; T3, 3,3*,5-triiodothyronine; T4, thyroxine. / 9j0c$$oc11 P13-8 of an immune response to a foreign antigen (sheep red blood cells), rats mount a parallel endocrine response characterized by elevated plasma levels of GC (corticosterone) (73). Furthermore, mice injected with supernatants from concanavalin A-stimulated peripheral blood or spleen cells produce one or more GC-increasing factors (GIF) that increase the blood concentrations of corticosterone (68). These studies therefore suggested the existence of an immune-neuroendocrine regulatory feedback mechanism in which immune cells limited their own activity by secreting molecules that stimulate the secretion of adrenal GC. The concept of ‘‘bidirectional communication’’ between immune and endocrine systems became firmly established with the seminal works of Edwin Blalock and co-workers in the early 1980s. These workers began to describe molecular basis for such bidirectional communication (reviewed in Refs. 80–82, 952, 953). Their early studies showed a commonality in the pathways of action of immunoregulators (e.g., interferon) and hormones (e.g., norepinephrine) (84). This group went on to discover that a number of classical hormones are not only secreted by classical endocrine glands (e.g., pituitary) but are also made by cells of the immune system (e.g., lymphocytes). For example, they showed that lymphocytes synthesize ACTH, the pituitary hormone which is the major physiological regulator of adrenal GC secretion (792). In addition, they demonstrated that not only do lymphocytes produce hormones such as ACTH, endorphins, thyrotropin, and growth hormone (792, 794, 951) but that these hormones were able to influence immunologic processes (79, 83, 370, 371). Subsequent studies have demonstrated that a number of hormones (e.g., prolactin, insulinlike growth factor) are produced by lymphocytes (372, 556, 557, 621). 11-25-98 11:16:36 pra APS-Phys Rev Downloaded from on April 23, 2014 1940s, and the demonstration of its ability to suppress inflammation (335), gave support to the hypothesis that adrenal glucocorticoid (GC) secretion plays a significant role in regulating immunologic processes. However, even though marked elevations in the plasma blood concentration of GC are observed after all types of stressful stimuli, studies showing that GC produce immunosuppression were assumed (by the majority of workers) to be of pharmacological, rather than of physiological, significance. These findings advented the widespread use of GC-based therapies for autoimmune and inflammatory disease. It was not until the late 1970s and the pioneering work of Besedovsky, del Rey, Sorkin, and colleagues that a physiological role for GC in preventing overactivity, and preserving the specificity, of immune reactions became established (67, 191). In a significant review article of the early 1980s, Munck et al. (567) reinforced this concept. These authors proposed the now commonly held view that endogenous GC act to prevent ‘‘overshoot’’ of immune/inflammatory responses, thus limiting the host defense response to fighting the aggressor (e.g., invading pathogen) without the deleterious effects to the host of a hyperactive immune system (e.g., autoimmunity). More recent work has indicated that the influence of GC on immunologic processes is more complex than a generalized suppression of immune activity and depends on the type of immune activity and the subset of immunologic cells involved (see Ref. 531 for extensive review). However, it is clear that endogenous GC are key regulators of immune system function. Further work by Besedovsky et al. (73) suggested that not only do GC have a profound impact on immune activity, but that the converse is also true and immune activity influences GC secretion. This hypothesis grew out of experimental observations that during the development 4 ANDREW V. TURNBULL AND CATHERINE L. RIVIER 1 Interleukin literally means ‘‘between leukocytes.’’ / 9j0c$$oc11 P13-8 resulted in articles being published back to back in a 1987 issue of Science (55, 62, 730). One of these studies (62) demonstrated a direct action of IL-1 on ACTH secretion from primary cell cultures of rat anterior pituitary cells, thus supporting the earlier studies by Blalock and coworkers (966) suggesting a direct action of IL-1 on the pituitary gland to secrete ACTH. Conversely, the other two Science papers (55, 730) found that IL-1 does not stimulate ACTH secretion from anterior pituitary cells in primary culture, despite the fact that IL-1 in vivo elevates plasma ACTH and GC concentrations. These latter two groups (55, 730) showed that IL-1-induced ACTH secretion in vivo is dependent on the secretion and action of the hypothalamic 41-amino acid peptide CRF, which is the major hypothalamic ACTH secretagogue. These findings clearly implicate the hypothalamus as the site at which the HPA axis response to IL-1 is mediated and gave great support to the idea that immunoregulators could influence the activity of the central nervous system (CNS). Controversy over the likely primary site of IL-1 action (CNS, pituitary gland, or possibly adrenal glands) in stimulating pituitary-adrenal secretion has continued for many years and is considered in detail in sections IV and V. However, a large body of evidence has now accumulated that indicates that IL-1 and other cytokines can signal the brain. In parallel with studies investigating the relationship between the immune system and HPA axis, a large number of studies indicated that fever caused by invading pathogens occurs as a result of the elaboration from immune cells of an ‘‘endogenous pyrogen’’ capable of signaling the CNS (reviewed in Refs. 23, 420). This endogenous pyrogen was putatively identified as IL-1 (reviewed in Ref. 420). Furthermore, administration of IL-1 produces many CNS-mediated changes including changes in behavior (reduced exploration, reproductive activity, food-motivated behavior, and increased sleep), changes in autonomic outflow, metabolic rate, and the activity of a number of neuroendocrine axes (see Refs. 54, 65, 408, 409, 439, 440, 529, 683, 708 for relevant reviews). Collectively, these studies have provided strong evidence for the regulation by IL-1 of CNS responses to peripheral changes in immune activity. Furthermore, the common mediator of the effects on various CNS responses provides a molecular basis for the observations of the stereotypical responses to immune challenges of diverse origins. This ‘‘acute phase response’’ to sickness is characterized by fever, appetite suppression, anorexia, alterations in plasma cation concentrations, synthesis of specific liver proteins (known as acute phase proteins), and changes in neuroendocrine secretions (441). It is now firmly established that acute phase responses are produced by the actions of, and complex interactions between, IL-1 and numerous other cytokines. Since the landmark studies by the groups of Besedovsky and Blalock, it has become apparent that IL-1 has potent effects on the secretion of the majority of hor- 11-25-98 11:16:36 pra APS-Phys Rev Downloaded from on April 23, 2014 The finding that lymphocytes are able to synthesize an ACTH-like molecule, combined with the demonstration that mice whose pituitary gland had been removed (hypophysectomy) still produced a corticosterone response to infection with the Newcastle disease virus (NDV), led Blalock and co-workers (793) to propose the concept of lymphoid-adrenal axis. According to this hypothesis, ACTH produced by virus-stimulated lymphocytes acts on the adrenal to increase corticosterone secretion. However, subsequent studies have failed to replicate the persistance of an NDV-induced corticosterone response in hypophysectomized mice (64, 218, 221, 604), and the hypothesis of a lymphoid-adrenal axis involving lymphoid production of ACTH molecule has fallen out of favor. Furthermore, Besedovsky et al. (71) showed that stimulated lymphocytes secrete GIF that increase plasma ACTH and corticosterone levels in rats and that this corticosterone response was prevented by hypophysectomy. Given that the electrical and neurochemical activities of the hypothalamus are also altered during the course of an immune response (69, 72), Besedovsky et al. (71) proposed that the effects of such GIF on adrenal GC secretion were probably mediated at the hypothalamic component of the hypothalamic-pituitary-adrenal (HPA) axis, rather than on the pituitary or adrenal glands directly. The chemical identity of putative ‘‘GIF’’ became apparent with the recognition that classical endocrine hormones are not the only class of mediators involved in immune-endocrine communication. Indeed, in the mid 1980s, it became readily apparent that immunoregulatory cytokines also form a key link between immune and neuroendocrine systems (70, 331, 532, 966). Blalock and coworkers (966) showed that the monokines interleukin (IL)-1 and IL-6 (or hepatocyte-stimulating factor) stimulate ACTH secretion from the corticotropic tumor cell line AtT20.1 A year later, Besedovsky et al. (70) demonstrated that systemic administration of monocyte-derived or recombinant IL-1 increases plasma ACTH and GC concentrations in normal mice. Furthermore, Besedovsky et al. (70) demonstrated that neutralization of endogenous IL1 inhibits the GC response to experimental viral infection (NDV) in rats. This latter experiment clearly indicated that the observations of stimulatory effects of cytokines on neuroendocrine secretion were not merely pharmacological phenomena and suggested that IL-1 plays an important endogenous role in regulating the HPA axis during viral disease. Indeed, these landmark studies by Besedovsky and Blalock indicated that cytokines could be the extrahypothalamic corticotropin-releasing factors (CRF) released by injured tissue which had previously been reported by Broddish and co-workers during the 1970s (112, 113, 497). Subsequent work by three independent laboratories Volume 79 January 1999 REGULATION OF HPA AXIS BY CYTOKINES 2. Influence of interleukin-1 on neuroendocrine secretion TABLE Neuroendocrine System Hypothalamic-pituitaryadrenal axis Hypothalamic-pituitarygonadal axis Hypothalamic-pituitarythyroid axis Somatotropic axis Prolactin secretion Posterior pituitary hormone secretion Catecholamines Effect Reference No. Increases secretion 863, 883, 959 Decreases secretion 683, 715, 882, 886 336, 358, 665, 886 634, 922 Decreases secretion Increases or decreases secretion Increases or decreases secretion Increases secretion 671, 689 158, 159, 446, 992 54, 695 Increases secretion C. Cytokines 1. Cytokines and cytokine receptor families Cytokines are large (8–60 kDa), soluble polypeptide mediators that regulate growth, differentiation, and function of many different cell types (see Table 3). The majority of cytokines have been classically associated with the regulation of immune and/or inflammatory processes, and within the immune system, their actions are generally exerted in paracrine or autocrine fashions. However, because of the demonstration that immune, central nervous, and neuroendocrine systems share a common chemical language, much more diverse actions of cytokines in host / 9j0c$$oc11 P13-8 defense are now recognized. Accordingly, the expression of these polypeptides and their receptors is not restricted to cells of the immune system but is also found in many other tissues (including the brain and endocrine glands). Furthermore, many cytokines exert potent actions on a variety of physiological activities outside of immunoregulation; for example, many cytokines induce fever, sleep, anorexia, malaise, and alterations in neuroendocrine secretions. Finally, the ability of some cytokines to regulate homeostatic processes at tissues distant from their site of production has firmly established cytokines as key regulators of coordinated local and systemic responses to tissue trauma, infection, and disease. The classification of cytokines into families has proven somewhat arbitrary. With the exception of a few homologous peptides (e.g., IL-1a and -1b; interferon-a and -b; and tumor necrosis factor-a, -b) most cytokines share little sequence similarity. Consequently, classification of cytokines has been based on either functional attributes, target receptors, or cells of origin. Most commonly, cytokines have been classified into families of interleukins, tumor necrosis factors (TNF), interferons (IFN), chemokines, hematopoietins (or neuropoietins), and colony-stimulating factors (CSF). Because of their similar actions particularly within the CNS and peripheral nervous system, growth factors (GF) and neurotrophins (NT) have also been considered to fall under the umbrella term cytokine. Their overlapping actions lead to a number of cytokines belonging to more than one family (see Table 3). For example, IL-6 is not only an interleukin, but also a member of a family of either hematopoietic or (neuropoietic) factors that utilize an identical receptor subunit (gp130) for cell signaling (416). Furthermore, IL-1, IL-3, IL-5, and IL-6 are also CSF. One of the striking features of cytokines is their ability to exert many different actions (a property known as ‘‘pleiotropy’’) and, conversely, that many different cytokines exert the same biological actions (a property known as ‘‘redundancy’’) (162, 633). Cytokine pleiotropy presumably relates to the widespread distribution of cytokine receptors on numerous cell types and the ability of signal transduction mechanisms activated by cytokines to alter expression of a wide variety of target genes. The functional redundancy of various cytokines has, at least partially, been explained by the identification and molecular cloning of many cytokine receptors. Some, although certainly not all, cytokine receptors consist of a multiunit complex, including a cytokine-specific ligand binding component and a ‘‘class’’-specific signal transduction unit (416, 733). In addition to the gp130 signaling cytokines, common receptor subunits have also been demonstrated for IL-2, IL-4, and IL-7 (733) and also for IL-3, IL-5, and granulocyte-macrophage CSF which share the signal transduction subunit KH7 (552). However, cytokine redundancy cannot be totally explained by the sharing of 11-25-98 11:16:36 pra APS-Phys Rev Downloaded from on April 23, 2014 mones under neuroendocrine control (see Table 2). Furthermore, more recent studies have shown that alterations in neuroendocrine secretion are produced not only by IL1, but also by many other immunoreglatory cytokines. The HPA axis has remained the most extensively studied neuroendocrine system with respect to the influence of cytokines, and the ability to increase the secretory activity of this axis is a biological property of several interleukins, tumor necrosis factors, chemokines, hematopoietins, interferons, growth factors, and neurotrophic factors. This article reviews published findings that demonstrate 1) which cytokines influence hormone secretion from the HPA axis, 2) under what physiological/pathophysiological circumstances endogenous cytokines may influence HPA axis secretory activity, 3) at which level (hypothalamus, pituitary, or adrenal) cytokines primarily act, and 4) what anatomic and pharmacological pathways mediate the actions of cytokines on the neuroendocrine hypothalamus. To achieve this aim, we have divided this article into sections corresponding to these overall objectives. We begin by providing brief introductions to relevant aspects of cytokine biology (see sect. IC) and the functional anatomy of the HPA axis (see sect. ID). 5 6 ANDREW V. TURNBULL AND CATHERINE L. RIVIER TABLE Volume 79 3. Cytokine families Family Members Major Ascribed Actions Interleukins IL-1 to IL-18 Tumor necrosis factors TNF-a, TNF-b Interferons Chemokines IFN-a, -b, -g IL-8/cinc/gro/NAP-1, MIP-1a, -b, RANTES IL-6, CNTF, LIF, OM, IL-11, CT-1 G-CSF, M-CSF, GM-CSF, SCF, IL-3, IL-5 Hematopoietins (neuropoietins) Colony stimulating factors Neurotrophins NGF, BDNF, GDNF, NT-3, NT-6 IGF-I, IGF-II, EGF, aFGF, bFGF, PDGF, TGF-a, TGF-b, activin Growth factors Categorization as an IL does not imply function; IL have numerous and diverse immunoregulatory actions; some IL have clearly proinflammatory actions (e.g., IL-1a, IL-1b, IL-8, IL-9), whereas others have antiinflammatory effects (e.g., IL-1ra, IL-4, IL-10, IL-13). Many IL also induce systemic aspects of acute phase response (e.g., fever) Tumor cytotoxicity; broad-ranging immunologic activities; induction of many other cytokines; immunostimulant; proximal mediator of inflammatory response Inhibit viral replication; regulation of specificity of immune responses Chemotaxis; activation of cells at inflammatory sites All utilize gp130 receptor subunit for signaling; various actions on B cells and other immunoregulatory actions; promote survival of neurons Promotion of growth and differentiation of multipotential progenitor cells in bone marrow; increase numbers of, or enhance activity of, cells of granulocyte, macrophage, and eosinophil lineages Neuronal growth and differentiation Cell growth and differentiation receptor subunits, since a number of cytokines, for example, IL-1, IL-6, and TNF-a, have many common biological activities despite the utilization of distinct cell surface receptors (see Table 4). Although there is some evidence that cytokines may play a role in some ‘‘normal’’ physiological processes such as sleep (605, 606, 838, 839), exercise (138, 139, 815, 920), and ovulation (2, 137), the expression of most cytokines in most normal healthy tissues is very low. However, cytokine production increases markedly during ‘‘tissue stress’’ produced by diverse cellular challenges, including periods 4. Shared biological activities of IL-1, IL-6, and TNF-a TABLE Immunologic properties T-cell activation B-cell activation Nonspecific resistance to infection Neuroendocrine actions Activation of the hypothalamic-pituitary-adrenal axis Suppression of the hypothalamic-pituitary-gonadal axis Suppression of the hypothalamic-pituitary-thyroidal axis CNS activities Fever Hypermetabolism Anorexia Effects on liver Acute phase protein synthesis CNS, central nervous system. / 9j0c$$oc11 P13-8 of rapid cellular growth, tissue remodeling, disease, infection, or trauma. The particular cytokines produced in response to a threat to tissue homeostasis depends on the nature of the threat (e.g., bacterial, viral, inflammatory), the cellular or tissue type being threatened, the hormone milieu, and to a large extent the profile of other cytokines that are being produced. A further striking feature of cytokines is the multiple interactions between different individual cytokines. Many types of interactions are apparent, including stimulatory or inhibitory actions at the level of cytokine synthesis. For example, the proinflammatory cytokines TNF-a and IL-1 potently stimulate the production of a number of other cytokines, including each other, as well as IL-6, IL8, IL-9, macrophage inflammatory protein (MIP), and CSF (206). In contrast, anti-inflammatory cytokines such as IL-4, IL-10, and IL-13 abrogate the production of many proinflammatory cytokines (e.g., IL-1, IL-8, IL-12, TNF-a, IFN-g, and CSF) (122, 563), whereas IL-6 inhibits the production of IL-1 and TNF-a but stimulates the production of the endogenous IL-1 receptor antagonist IL-1ra (379, 743). Furthermore, there are numerous examples of a particular cytokine influencing the cellular responses to another cytokine. For example, nearly all biological responses to either TNF-a or IL-1 can be enhanced when the two are administered together (206), whereas activin functionally antagonizes the actions of gp130-signaling cytokines (114). The great propensity for cytokine-cytokine 11-25-98 11:16:36 pra APS-Phys Rev Downloaded from on April 23, 2014 aFGF, acidic fibroblast growth factor; BDNF, brain-derived neurotrophic factor; bFGF, basic fibroblast growth factor; cinc, cytokine-induced neutrophil chemoattractant; CNTF, ciliary neurotrophic factor; CT-1, cardiotropin-1; EGF, epidermal growth factor; G-CSF, granulocyte colony stimulating factor; GDNF, glial-derived neurotrophic factor; GM-CSF, granulocyte-macrophage colony stimulating factor; gro, growth-related oncogene; IGF, insulin-like growth factor; IL, interleukin; IL-1ra, IL-1 receptor antagonist; IFN, interferon; LIF, leukemia inhibitory factor; M-CSF, macrophage colony stimulating factor; MIP, macrophage inflammatory protein; NAP, neutrophil activating protein; NGF, nerve growth factor; NT, neurotrophin; OM, oncostatin M; PDGF, platelet-derived growth factor; RANTES, regulated upon activation normal and secreted; SCF, stem cell factor; TGF, transforming growth factor; TNF, tumor necrosis factor. January 1999 REGULATION OF HPA AXIS BY CYTOKINES interactions is illustrated by the large number of different cytokines that may be produced by a single threat to cellular/tissue homeostasis. For example, endotoxemia has been reported to cause the increased synthesis and/or secretion of IL-1a, IL-1b, IL-1ra, IL-6, IL-8, IL-10, IL-12, TNF-a, MIP, macrophage migrating inhibitory factor (MIF), IFN-g, leukemia inhibitory factor (LIF), and granulocyte-macrophage CSF. It is therefore apparent that during the course of a threat to tissue homeostasis, the physiological outcome is determined by the net effect of the interactions between a number of cytokines. Although many different cytokines have been shown to influence HPA axis secretory activity, by far the majority of studies have focused on the cytokines IL-1, IL-6 and TNF-a. These three cytokines share many biological activities (see Table 4). Section IC2 gives a brief outline of their structure, biosynthesis, and receptors. 2. IL-1, IL-6, and TNF-a / 9j0c$$oc11 P13-8 munoglobulin supergene family and possess a single transmembrane domain. Each receptor binds IL-1a, IL1b, and IL-1ra, but with differing affinities (784). It has been proposed that the biological actions of IL-1 are mediated exclusively through IL-1R1 (442, 785), with IL-1R2 functioning solely as a decoy receptor that limits the availability of IL-1 for interaction with IL-1R1 (163, 784, 786). In contrast, some studies have demonstrated that a monoclonal antibody (ALVA 42) raised against IL-1R2 inhibits some actions of IL-1 within the brain (493, 548), although the ability of this antibody to bind IL-1R2 has been questioned (282). In addition to the two receptor isoforms, an accessory protein (IL-1RAcP) has been identified that enhances binding of IL-1 to IL-1R1 (304, 482) and plays a critical role in cell signaling through this receptor (348, 433, 994). Several additional members of the IL-1 receptor family have been identified on the basis of sequence homology (53, 94, 278, 488, 489, 550, 627, 989). One of these proteins (IL-1 receptor-related protein, IL-1Rrp) has recently been identified as a functional receptor for IGIF/ IL-18/IL-1g (869). Tumor necrosis factor also occurs in a- and b-forms, which share Ç50% homology. Tumor necrosis factor-b (lymphotoxin-a) is produced predominantly by activated lymphocytes. In contrast, TNF-a (also known as cachectin) is expressed on a wide variety of hemopoietic and nonhemopoietic cells as a 26-kDa membrane-associated molecule. This can be processed to give a secreted 17-kDa soluble form that mediates a range of inflammatory and cellular immune responses. Tumor necrosis factor is one of 10 known members of a family of ligands that activate a family of structurally related receptors. These include receptors for TNF-a and TNF-b, lymphotoxin-b, Fas ligand, nerve growth factor (NGF), and CD40 ligand (47). All the ligands for these receptors consist of three polypeptide chains, and the majority are transmembrane proteins that act mainly through cell-to-cell contact. However, TNF, as indicated, is also secreted. Actions of TNF-a are exerted through interactions with two distinct receptors: the 55-kDa (TNF-R1) and 75kDa (TNF-R2) receptors (47). These two receptors are both transmembrane proteins with a single transmembrane span and are expressed at low levels on most cell types. Although the extracellular domains of these two receptors show a similar architecture, the intracellular domains of these two receptors bear no significant homology, suggesting that they utilize separate signaling pathways (467). Indeed, studies of the effects of receptorspecific agonistic antibodies (233, 241, 283, 851, 968) and of TNF-R-deficient mice (234, 642, 707) indicate that these two receptors mediate effects that are largely, but not exclusively, nonoverlapping. Recent molecular studies have shed a considerable light on the activities of the two receptors (reviewed in Ref. 182). Binding of TNF to either receptor activates the proinflammatory transcription fac- 11-25-98 11:16:36 pra APS-Phys Rev Downloaded from on April 23, 2014 There are at least three distinct glycoproteins that constitute the IL-1 family. The two agonists, IL-1a and IL-1b, share Ç25% sequence homology, are distinct gene products, and exhibit the same activities in numerous biological test systems (205). Both are synthesized as 31-kDa precursor molecules. Pro-IL-1b is biologically inactive and requires proteolytic cleavage by the IL-1b converting enzyme (ICE, also known as caspase-1) (401). In addition, an endogenous antagonist at IL-1 receptors (IL-1ra) has been described, which shares significant homology with IL-1a and IL-1b, binds IL-1 receptors, but lacks intrinsic biological activity (225, 318). Interleukin-1ra has been used extensively as a pharmacological tool to explore the role of IL-1-IL-1 receptor interactions in physiological responses (203). More interestingly, however, endogenous IL-1ra is secreted by similar cell types, and in response to similar stimuli, as those which produce the IL-1 agonists, and endogenous IL-1ra plays an important role in regulating the physiological responses to endogenous IL1 (260, 485). Recently, a fourth member of the IL-1 family has been proposed. Structural alignment of mouse IL-18 (also known as IFN-g inducing factor, IGIF) demonstrated a 12 and 19% structural homology of this newly cloned cytokine with IL-1b and IL-1a, respectively (46). Interleukin-18 was thus tentatively termed IL-1g (46). Although there is, as yet, little information about this new cytokine (850), it is known that lipopolysaccharide (LPS)-stimulated production of mature IL-18/IL-1g requires ICE (249, 287, 307). Furthermore, IL-18/IL-1g and IL-1 itself share similar signaling pathways (428) and functional activities (351), again indicating a close relationship between this novel cytokine and the IL-1 family. Two distinct mammalian, membrane-bound IL-1 receptors have been described and designated IL-1R1 and IL-1R2 (784). Both are glycoproteins belonging to the im- 7 8 ANDREW V. TURNBULL AND CATHERINE L. RIVIER / 9j0c$$oc11 P13-8 and TNF soluble receptors to bind their ligands limits the availability of either IL-1 or TNF-a for interaction with their membrane-bound receptors and therefore confers antagonistic properties to these truncated receptors. In contrast, the soluble IL-6 receptor, upon binding its ligand, can interact with gp130 and elicit a cellular response. Indeed, coincubation of IL-6 with its soluble receptor has been demonstrated to confer IL-6 sensitivity to previously IL-6-insensitive cells and enhances the effectiveness of IL6 in vivo (506, 641, 747). Thus the biological activity of a particular cytokine is determined not only by its own concentration and the concentration of cytokines which influence its activity but also by the presence of its soluble receptor. D. Hypothalamic-Pituitary-Adrenal Axis 1. HPA axis organization Over the last 10–15 years, there have been over 1,000 published articles concerning the activation of the HPA axis by cytokines. This relative abundance of work is due to the large number of cytokines discovered, the complexity of the organization of the HPA axis (see Fig. 1), and the functional importance of activation of the HPA axis during stressful situations. Basal secretion of GC is necessary for the normal function of most tissues, and even small deviations from normal circulating levels of these steroids produce changes in a wide variety of physiological and biochemical parameters. Interactions between the endocrine system and the CNS result in a diurnal rhythm of GC secretion with a peak occurring at the time of awakening and a nadir during the first few hours of sleep. Blood levels of circulating GC increase in response to virtually any type of stimulus that poses, or is perceived to pose, a threat to bodily homeostasis. Glucocorticoids act on multiple targets to enhance or inhibit various cellular activities, actions that are aimed at providing the altered metabolic, endocrine, nervous, cardiovascular, and immunologic needs that promote survival. Not surprisingly, therefore, the regulation of blood levels of GC is subject to diverse sensory inputs, and this information is integrated at the level of the hypothalamus. The primary CNS nucleus involved in the regulation of pituitary-adrenal axis is the paraventricular nucleus (PVN) of the hypothalamus. The PVN is the principal CNS source of the 41-amino acid peptide CRF, which is the major physiological regulator of pituitary ACTH secretion (691). The CRF hypophysiotropic neurons from the PVN project to the external zone of the median eminence (ME) and release CRF into a specialized capillary network. The anterior pituitary (or adenohypophysis) is vascularized by hypophysial portal vessels that arise from these median eminence capillary beds. Within the anterior pituitary, CRF interacts with a specific G protein-coupled receptor 11-25-98 11:16:36 pra APS-Phys Rev Downloaded from on April 23, 2014 tor NFkB. In the case of TNF-R2, signal transduction occurs via heteterodimerization of the receptor with two TNF-R2 associated factors, TRAF1 and TRAF2, and it is TRAF2 that appears to mediate TNF-R2-induced activation of NFkB. In contrast, TNF-R1, upon ligand binding, recruits a protein called TRADD. Like TRAF2, TRADD causes NFkB activation but, unlike TRAF2, also causes apoptosis via an ICE-like protease. This explains why TNF-R1, but not TNF-R2, causes apoptosis. However, the NH2-terminal domain of TRADD interacts directly with TRAF2, and overexpression of a dominant negative TRAF2 blocks not only TNF-R2 but also TNF-R1-induced NFkB activation. Thus activation of the two TNF receptors elicits separate signaling pathways that can interact with one another, thus explaining the distinct and overlapping signals generated by the two TNF receptors. Interleukin-6 is a single 21- to 28-kDa glycoprotein produced by both lymphoid and nonlymphoid cells and regulates immune responses, acute-phase protein synthesis, and hematopoiesis. Human IL-6 is synthesized as a precursor polypeptide of 212 amino acids that is processed by cleavage of a 28-amino acid NH2-terminal signal sequence into a mature form of 184 amino acids. One IL-6 receptor has thus far been identified. This IL-6 specific receptor (IL-6Ra) is responsible only for binding of its ligand (IL-6). Interleukin-6 belongs to a family of cytokines that includes ciliary neurotropic factor (CNTF), oncostatin M (OM), LIF, IL-11, and cardiotropin1 (CT-1), which share a common signal-transducing mechanism (reviewed in Refs. 415, 416). All these cytokines are bound by receptors that interact with the common cell-surface protein gp130. Ligand-receptor complexes that share gp130 trigger signaling by the formation of either homodimers of gp130 or heterodimers between gp130 and LIFR. In the case of IL-6, signaling is initiated by the homodimerization of gp130 induced by the interaction with the IL-6/IL-6Ra complex. Either homodimerization of gp130 or heterodimerization of gp130 with LIFR activates JAK kinases, followed by the tyrosine-specific phosphorylation and nuclear translocation of a member of the STAT family (STAT3) of transcription factors. In addition, there is another signaling pathway that involves the activation of the RAS-MAP kinase cascade followed by the activation of transcription factors such as nuclear factorIL-6 (NF-IL-6). Such sharing of receptor complexes and subsequent activation of similar signaling pathways by members of the IL-6 family of cytokines is a clear example of how a number of different cytokines display similar biological activities (i.e., cytokine redundancy). Receptors for IL-1, IL-6, and TNF-a occur not only in membrane-bound forms, but also as truncated soluble products, which are capable of binding their ligand (257, 332, 703). These receptors are generated either by proteolytic cleavage at the cell surface or are synthesized as alternatively spliced mRNA species. The ability of IL-1 Volume 79 January 1999 REGULATION OF HPA AXIS BY CYTOKINES (CRF-R1) on the corticotrope cell surface, resulting in the stimulation of the synthesis of the ACTH precursor peptide proopiomelanocortin (POMC) and the secretion of ACTH and other POMC-derived peptides (888, 898). Adrenocorticotropin hormone potently induces the secretion of GC from the zona fasciculata of the adrenal cortex. In humans, the major GC is cortisol, but in the rat and mouse, corticosterone is the main steroid product of the zona fasciculata. In a classical endocrine feedback manner, these steroids inhibit the synthesis and secretion of CRF within the hypothalamus and POMC-derived peptides in the pituitary (404, 995). The PVN has an anatomically discrete topography but functionally and phenotypically overlapping organization. The PVN is comprised of two major neurosecretory subdivisions; the magnocellular (mPVN) and parvocellular (pPVN) divisions, as well as more caudal cell groups giv- / 9j0c$$oc11 P13-8 ing rise to long descending projections to brain stem autonomic structures (738). The mPVN together with the supraoptic nucleus (SON) constitute the magnocellular neurons that are the major cell sources of arginine vasopressin (AVP) and oxytocin released into the general circulation from neurons terminating in the posterior pituitary. The more medially situated pPVN is the major source of hypophysiotropic CRF neurons, which release CRF into the hypophysial portal circulation. The cell groups projecting to autonomic structures contain all three peptides (CRF, AVP, and oxytocin). However, although these subdivisions of PVN are anatomically discrete, the PVN does display considerable peptide phenotype plasticity. The CRF hypophysiotropic neurons also produce a number of additional peptides, most notably AVP (740, 864), which interacts synergistically with CRF to stimulate ACTH secretion (693), and whose synthesis in these neurons can be enhanced during increased pituitaryadrenal activity (738). Furthermore, AVP and oxytocin derived from sources other than the pPVN may also contribute to the pool of ACTH secretagogues in hypophysial portal blood (15, 648, 651). Therefore, although it is generally agreed that CRF arising from the pPVN is the major means of stimulating ACTH secretion, this is not an absolute, with AVP (and possibly oxytocin) secretion from either pPVN or magnocellular neurons contributing to an extent that varies with the nature of the physiological threat. Consistent with the extreme diversity of stressful stimuli that give rise to activation of the HPA axis, the pPVN receives diverse inputs from regions of the brain conveying visceral, somatosensory, auditory, nociceptive, and visual information and also from limbic regions involved in the integration of cognitive and emotional influences (738). These inputs include projections from other nuclei within the hypothalamus (e.g., medial preoptic anterior hypothalamus). Extrahypothalamic inputs include areas both within [e.g., nucleus of the solitary tract (NTS) and other medullary catecholaminergic cell groups] and outside [organum vascularis of the lamina terminalis (OVLT) and subfornical organ (SFO)] the blood-brain barrier (BBB) (738). There are, therefore, multiple levels at which the activity of the HPA axis may be modulated, and indeed, virtually all the regulatory processes described above have been proposed as sites at which cytokines regulate HPA axis activity. 2. Experimental assessment of the HPA axis secretory activity The measurable end points and experimental methodologies that have been used to examine the secretory activity of the HPA axis in response to cytokines are extremely diverse and shall be considered here briefly. The net result of increased HPA axis secretory activity is the 11-25-98 11:16:36 pra APS-Phys Rev Downloaded from on April 23, 2014 FIG. 1. Functional anatomy of hypothalamic-pituitary-adrenal axis. AVP, arginine vasopressin; CRF, corticotropin-releasing factor; I.H., inferior hypophysial; S.H., superior hypophysial. 9 10 ANDREW V. TURNBULL AND CATHERINE L. RIVIER / 9j0c$$oc11 P13-8 of either hypothalami, anterior pituitaries, or adrenals, with the tissue being intact (whole), in segments or slices, or in dispersed monolayer cell culture. These methodologies produce a more isolated environment in which to define direct actions of applied substances. II. CYTOKINE INFLUENCE ON HYPOTHALAMIC-PITUITARY-ADRENAL AXIS SECRETORY ACTIVITY IN VIVO A. Animal Studies Numerous studies have confirmed and extended the original findings that the administration of either IL-1a or IL-1b to rats or mice stimulates ACTH and GC secretion, as well as many other indices of HPA activation (see Table 5). In addition, IL-1 has been demonstrated to increase the secretory activity of the HPA axis of chickens (959), sheep (916), baboons (674), and humans (see sect. IIB). Studies addressing interactions between cytokines and neuroendocrine systems in an invertebrate species (snail) have demonstrated the presence of a rudimentary stress system involving CRF-, ACTH-, and bioamine-like molecules in immunocytes (613 – 616). The snail immunocyte stress system contains, and is responsive to, cytokines, including IL-1, IL2, and TNF-a (612, 615 – 617). Activation of the HPA axis (or invertebrate equivalent) by IL-1 has therefore been highly conserved throughout evolution in different species and taxa, indicating the importance of this adaptive response to survival (615). In mammals, the ACTH response to intravenous IL-1 is usually prompt, commencing within 5–10 min, and of relatively short duration (Ç1 h). In comparison, the plasma ACTH response to intraperitoneal injection of IL1b is slower in onset, but usually of longer duration (at least 2 h). Finally, the response to IL-1 administered directly into the brain (intracerebroventricularly) is of intermediate latency and lasts for several hours (usually greater than 3–4 h). The majority of studies have found IL-1b to be more potent than IL-1a in the rat (525, 574, 690, 695). Studies utilizing a panel of monoclonal antibodies have demonstrated that amino acids in the domain 66–85 on the recombinant rat IL-1b molecule are critical for its ACTH-releasing capacity (751). In the rat, IL-1b stimulates ACTH secretion at all stages of postnatal development of both males and females, although the magnitude of the ACTH response depends on age and gender (59, 192, 466, 598, 686). A single administration of IL-1b not only acutely elevates plasma ACTH and corticosterone concentrations in the rat, but has been demonstrated to produce a longlasting (at least 3 wk) increase in the coexpression of AVP in hypothalamic CRF neurons and a hyperresponsiveness 11-25-98 11:16:36 pra APS-Phys Rev Downloaded from on April 23, 2014 elevated concentrations of ACTH and GC in blood. Temporal measures of immunoreactive levels of these hormones have been widely adopted as means of studying the influence of cytokines on the HPA axis and are the main method suitable for use in humans. Furthermore, the determination in laboratory animals of the effects of various surgical, pharmacological, or genetic manipulations on the plasma hormone response to a given cytokine provides a valuable means to elucidate the anatomic and neurochemical mechanisms involved in the activation of the HPA axis by a particular cytokine. To assess the activity of neuronal components of the HPA axis in response to a particular cytokine, a number of methods have been employed, including the use of electrophysiological recordings and the histochemical determination of the expression of cellular immediate early genes (cIEG), such as c-fos. The demonstration of c-fos as an inducible and widely applicable marker of neuronal activity (558) has afforded a means of mapping neuronal activation in response to a variety of stimuli, including the administration of cytokines. In particular, the stressinduced induction of c-fos mRNA and/or Fos protein within the PVN has been thoroughly examined and validated as a means to identify activation of neurosecretory neurons (152, 436). Another cIEG, NGFI-B, has been used for similar purposes (152, 436). Identification of the peptide phenotype of cells within the PVN expressing cIEG provides a powerful means to identify the activation of particular neurosecretory neurons. However, it should be noted that at present we do not know how the induction of such transcription factors relates to transcriptional activity within the PVN. Indeed, of the three peptides CRF, AVP, and oxytocin, only the AVP gene includes an AP-1 response element that binds Fos-Jun dimers, but all three genes contain potential NGFI-B response elements (152). Functional assessments of the relative neurosecretory rates of peptides from hypophysial PVN neurons have also been perfomed by measuring 1) peptide concentrations directly in portal blood, 2) peptide concentrations in the perfusates from push-pull cannulas or microdialysis probes within the ME, and 3) peptide content of the ME of either normal animals or animals pretreated with colchicine to block axonal transport. Finally, determination of the expression of steady-state mRNA or primary transcript RNA (hnRNA) levels of either CRF or AVP within the PVN have also been well documented. To determine the direct effects of cytokines on particular components of the HPA axis, a number of in vitro methodologies have also been used. Only one cell line has been available to study the action of cytokines on the HPA axis, namely, the AtT20 mouse corticotropic tumor line, which has been used as a model for investigating the direct effects of cytokines on anterior pituitary corticotropes. By far the majority of in vitro studies have utilized static or perfused primary preparations Volume 79 January 1999 TABLE Cytokine IL-1a 5. Acute effects of cytokines on the HPA axis of laboratory animals Route Effect icv iv ip icv IL-2 iv icv ip IL-4 IL-6 ip iv OM CT-1 CNTF TNF-a ip icv ip ip ia ip ip ip ip iv IFN-a Activin icv ip, icv icv IL-11 IL-12 LIF EGF NGF SCF iv icv iv iv Reference No. CRF in portal blood Plasma ACTH, corticosterone CRF mRNA CRF content of ME POMC mRNA in anterior pituitary Plasma ACTH Plasma ACTH PVN c-fos mRNA or Fos protein PVN CRF mRNA CRF secretion from ME CRF content of ME Plasma ACTH, corticosterone PVN c-fos mRNA or Fos protein CRF PVN mRNA POMC mRNA in anterior pituitary POMC hnRNA in anterior pituitary ACTH content of anterior pituitary Plasma ACTH, corticosterone PVN c-fos mRNA or Fos protein PVN CRF mRNA PVN AVP mRNA CRF secretion from ME Plasma ACTH, corticosterone ACTH Electrical activity of PVN neurons Plasma ACTH*, corticosterone* POMC in anterior pituitary Hypothalamic vasopressin mRNA Hypothalamic oxytocin mRNA POMC in anterior pituitary PVN Fos protein Plasma ACTH, corticosterone Plasma ACTH, corticosterone Plasma ACTH, corticosterone Plasma corticosterone† Plasma corticosterone Plasma ACTH Plasma corticosterone† Plasma corticosterone† Plasma corticosterone† Plasma corticosterone† CRF secretion from ME Plasma ACTH, corticosterone Plasma ACTH or F Plasma corticosterone‡ CRF in portal blood Plasma ACTH Plasma ACTH, corticosterone Plasma ACTH, corticosterone Plasma ACTH, corticosterone PVN Fos protein Plasma ACTH, corticosterone 223, 525, 574, 629, 730 639, 640, 824 574, 695 55, 223, 237, 525, 527, 560, 824, 929, 932, 936, 940 63, 64, 70, 98, 187, 327, 466, 628, 686, 690, 752, 824 40, 187, 457, 681, 684, 692 574 76, 317 326, 623 326 527, 575, 589, 909 52, 327 499, 527, 859, 909 52 608 5 52 52 52 52, 246 58, 66, 223, 771, 772, 938 51, 673, 881 725, 726, 729 650 492, 551 551 618, 741, 836 435 Routes of administration: iv, intravenous; ia, intra-arterial; ip, intraperitoneal; icv, intracerebroventricular. PVN, paraventricular nucleus; ME, median eminence; POMC, proopiomelanocortin. Other definitions are as in Table 3. * Chronic (7-day) infusion. Significant increases in plasma ACTH concentration observed only during latter period of dark cycle. † At doses tested, each of these cytokines alone had no effect on plasma corticosterone, but each potentiated the corticosterone response to a submaximal dose of IL-1. ‡ Stimulation of corticosterone secretion was noted only at higher doses of IFN-a. of the HPA axis (744). Long-term administration of IL-1b to rats enhances CRF- and ACTH-like immunoreactivities in the hypothalamus and pituitary, respectively, increases adrenal weight (573), and elevates plasma ACTH concentrations for at least 7 days (573, 830, 908). In addition to IL-1, a number of other cytokines have / 9j0c$$oc11 P13-8 been demonstrated to influence HPA axis secretory activity in experimental in vivo paradigms (see Table 5). Activation of the HPA axis is not restricted to cytokines produced predominantly by myeloid (e.g., monocyte, macrophage) cells (e.g. IL-1), but also by cytokines produced by lymphoid (e.g., T lymphocytes) cells (e.g., IL-2). Where 11-25-98 11:16:36 pra APS-Phys Rev Downloaded from on April 23, 2014 F F F f F F F F F F f F F F F F f F F F F F F F F F F F F f F F F F F F F F F F F F F F f F F F F F F F iv ip IL-1b 11 REGULATION OF HPA AXIS BY CYTOKINES 12 ANDREW V. TURNBULL AND CATHERINE L. RIVIER / 9j0c$$oc11 P13-8 effects on the HPA axis of recombinant rat cytokines generated by this initiative had been published. Although pharmacological differences of cytokines from different species may seem to complicate interpretation of data, they can actually provide useful pharmacological tools. For example, the difference between the effects of intracerebroventricular mouse and human TNFa on plasma ACTH concentration may reflect the differing pharmacological profiles of the two identified TNF receptors, TNF-R1 and TNF-R2. Murine TNF-R1 has high affinity for either mouse or human TNF-a, whereas only mouse TNF-a is effective at TNF-R2 (334, 467, 505). Should the same pharmacology be true at rat TNF-a receptors, as has been suggested (817), then the increase in plasma ACTH concentrations induced by intracerebroventricular mouse, but not human, TNF-a indicates that TNF-R2 is the major receptor isoform involved in cerebral TNF-ainduced activation of the rat HPA axis. Although by far the majority of cytokines tested in animal studies have been found to exert stimulatory actions on the HPA axis (see Table 5), two cytokines (IL-4 and IFN-g) have been suggested to inhibit HPA axis activity in vivo. The anti-inflammatory cytokine IL-4 dose-dependently inhibits POMC mRNA expression in the anterior pituitary, without affecting CRF mRNA in the pPVN, suggesting a direct inhibitory action at the level of the pituitary (326). Interferon-g has also been suggested to inhibit HPA axis secretory activity, since the administration of low doses either intraperitoneally or intracerebroventricularly reduces plasma corticosterone levels and the electrical activity of neurons within the PVN (725, 726, 729). However, higher doses of IFN-g given intracerebroventricularly enhance plasma corticosterone levels (726), suggesting that the qualitative effects of IFN-g on HPA axis activity are dependent on the dose used. B. Human Studies In addition to the numerous studies of the effects of cytokines on the HPA axis of laboratory animals, the clinical trials of a number of cytokines as anticancer strategies have afforded the opportunity to detail their effects on the HPA axis of humans. Such clinical studies have permitted investigation of the effects of cytokines on the HPA axis in a homologous system (i.e., human cytokines in human subjects). Either intravenous or subcutaneous administration of IL-1a (179, 795), IL-1b (176, 179), IL-2 (24, 194, 479–481, 812), IL-6 (519, 520, 809), TNF-a (596) IFN-a (41, 289, 337, 565, 566, 702, 758), IFN-b (596), and IFN-g (342, 596, 810) elevates plasma ACTH and/or cortisol concentrations. As in laboratory animals, the stimulation of ACTH secretion produced by cytokines occurs rapidly: within 1 h of intravenous infusion or within 1–4 h of subcutaneous treatment. 11-25-98 11:16:36 pra APS-Phys Rev Downloaded from on April 23, 2014 studies have compared the potencies, IL-1b has generally been found to be the cytokine most potent at stimulating ACTH secretion (e.g., Refs. 66, 358, 527, 772). However, this is not necessarily of physiological significance, since when it is the levels of endogenous cytokines that are elevated, the relative concentrations of each cytokine is a major determinant of which cytokine is of greatest influence. For example, during local inflammation, IL-6, which is generally agreed to be a less potent HPA axis secretagogue than IL-1, is elevated to a greater extent and for greater periods of time than is IL-1. Additionally, at least some cytokines act synergistically to enhance ACTH secretion. For example, all hematopoietic cytokines (IL6, LIF, OM, CNTF, IL-11, and CT-1) enhance ACTH and/ or corticosterone secretion produced by IL-1 to an extent greater than can be accounted for by additive effects (52, 639, 1003). Similarly, TNF-a synergistically enhances ACTH release produced by IL-1b (907). A number of studies have produced contradictory data with respect to the effects of various cytokines on HPA axis secretory activity. Although a stimulatory effect of TNF-a on the rat HPA axis has not been disputed when the cytokine has been administered peripherally (58, 772, 909), contrasting data have been obtained when TNF-a has been administered directly into the brain (intracerebroventricular). For example, although we showed that intracerebroventricular TNF-a induces marked elevations in plasma ACTH concentrations in rats (881), a number of other investigators have found little or no effect (673, 772, 909). Such discrepancies may, at least in part, be explained by the use of cytokines of different species origin. In the example cited, we used murine TNF-a (881), whereas those reporting little or no effect of intracerebroventricular TNF-a on plasma ACTH levels used human TNF-a (673, 772, 909). Similarly, studies in mice (51) have shown that plasma corticosterone concentrations are elevated to a greater extent by intracerebroventricular murine TNF-a than by intracerebroventricular human TNFa. Species differences have also been noted with IL-6, and the human IL-6Ra recognizes human IL-6 but not mouse IL-6 (173, 905). The use of human or mouse cytokine preparations has been common due to their wide availability, yet the most commonly used species in the investigation of HPA axis activity is the rat. However, the previous limited availability of recombinant rat cytokines has meant that not many studies have investigated the effects of cytokines in a homologous system (rat cytokine in the rat). When rat IL-1a (574) and rat IL-1b (751) have been tested in rats, the intravenous injection of these cytokines produces a marked elevation in plasma ACTH levels. Recombinant rat cytokines have now become more widely available since the establishment of BIOMED 1 program ‘‘Cytokines in the brain’’ of the European Communities (headed by Dr. R. Dantzer, Bordeaux, France). However, at the time of submitting this review, no studies of the Volume 79 January 1999 REGULATION OF HPA AXIS BY CYTOKINES III. PHYSIOLOGICAL/PATHOPHYSIOLOGICAL CIRCUMSTANCES IN WHICH ENDOGENOUS CYTOKINES PLAY A ROLE IN REGULATION OF HYPOTHALAMIC-PITUITARY-ADRENAL AXIS There are a number of examples of injury, infection, and/or disease that are associated with increased cytokine production and concomitant elevations in HPA axis activity: head trauma (427, 611, 976), cerebral ischemia (stroke) (253, 367, 571), a number of autoimmune diseases (175, 239, 322–325, 347, 455, 539, 654, 959), psychiatric and dementia disorders (165, 302, 510, 896), acquired immune deficiency syndrome (AIDS) (636, 661, 763, 827, 954), and antigenic challenges (69, 72, 73). However, direct and clear evidence for the involvement of particular / 9j0c$$oc11 P13-8 cytokines in the HPA axis response to such insults has been limited to only a few cases (viral or bacterial infection, local tissue damage and inflammation, and acute physical/psychological stress). Furthermore, although numerous cytokines have been shown to influence the secretory activity of the HPA axis, the direct demonstration of cytokine involvement in physiological or pathophysiological HPA axis responses has been restricted largely to the cytokines IL-1, IL-6, and TNF-a. The following sections outline the types of threats to homeostasis that have been demonstrated to elicit activation of the HPA axis via mechanisms that depend critically on the endogenous elaboration of cytokines. A. Viral Disease 1. Newcastle disease virus The first direct evidence indicating that IL-1 participates in the HPA axis response to an immune challenge came from studies investigating the neuroendocrine responses to inoculation with NDV (70). Newcastle disease virus is a neutrotropic paramyxovirus which, when administered to rodents, produces symptoms of viral disease without the potential hazard of replication. Within 1–2 h of injection, NDV produces marked elevations in ACTH and corticosterone concentrations in the blood of mice (70, 219–221, 604, 793) or rats (685). The majority of studies demonstrate that the increase in corticosterone is abolished by hypophysectomy (218, 220, 221, 604), indicating the importance of the pituitary in the adrenal response. Furthermore, the ACTH response is completely prevented when rats are passively immunized against CRF (685), indicating that hypothalamic CRF regulates the pituitary ACTH response to NDV. The stimulation of the HPA axis by NDV appears to be produced not by the virus itself, but by mediators released by immune cells exposed to the virus. This is evidenced by the fact that the supernatants of cocultures of NDV with either human peripheral blood leukocytes (HPBL) or mouse spleen cells also elevate plasma corticosterone concentrations. Indeed, intraperitoneal injection of supernatant from NDV plus HPBL produces a fourfold increase in plasma corticosterone concentrations in rats (70). This plasma corticosterone response is prevented by preincubation of the NDV plus HPBL supernatant with a rabbit neutralizing anti-human IL-1 antibody (70). More recent studies have demonstrated that intraperitoneal administration of IL-1ra to mice virtually abolishes the elevations in plasma ACTH and corticosterone concentrations 2 h after NDV (221), confirming the obligatory role of IL-1 in the generation of the HPA axis response to this viral challenge. 2. Polyinosinic polycytidilic acid Polyinosinic polycytidilic acid (Poly I:C) is a synthetic, double-stranded polyribonucleotide commonly 11-25-98 11:16:36 pra APS-Phys Rev Downloaded from on April 23, 2014 A series of experiments (519, 520) in which cancer patients of good clinical performance were examined showed that IL-6 is a particularly potent activator of the HPA axis and that the human HPA axis is remarkably responsive to this cytokine. On the first treatment day, IL6 (30 mg/kg sc) induced marked elevations in plasma ACTH and cortisol concentrations, with peaks occurring at 1 and 2 h, respectively. Plasma ACTH concentrations returned to basal levels within 5 h, whereas plasma cortisol levels remained elevated for 24 h. By the seventh day of treatment, the ACTH response to IL-6 was markedly diminished, an effect that was probably due to increased negative feedback produced by persistently elevated plasma cortisol levels. The sustained secretory activity of the adrenal was accompanied by gross enlargement of the adrenal glands as assessed by computed tomographic scans. Subsequent studies demonstrated that as little as 0.3 mg/kg (intravenous) is already a maximal dose of IL6 (520). The magnitude of the plasma ACTH response to a first injection of IL-6 was greater than that reported with the standard tests of pituitary-adrenal function such as injection of ovine CRF or the insulin tolerance test. The relatively mild toxic effects of IL-6 led the authors to propose that IL-6 may provide a new means of testing pituitary-adrenal function (519) and to conduct additional studies in normal human subjects (876). In normal healthy males, IL-6 (subcutaneous) again produced substantial elevations in plasma ACTH and cortisol, with peaks in ACTH and cortisol levels observed at 60–90 and 90–120 min, respectively, and a minimal effective IL-6 dose of 1– 3 mg/kg (876). Overall, human and animal studies agree that many exogenously administered cytokines have marked stimulatory actions on HPA axis secretory activity and suggest that endogenous production of cytokines during homeostatic threats may well play a causal role in the elaboration of the accompanying HPA axis response. 13 14 ANDREW V. TURNBULL AND CATHERINE L. RIVIER Volume 79 used to mimic viral exposure. Injection of Poly I:C, like NDV, produces a rapid (within 1–2 h) activation of the HPA axis (544, 716). Although there have been only a few investigations of the HPA axis response to Poly I:C, it is apparent that CRF is an important mediator of this response, because Poly I:C-induced increases in rabbit plasma cortisol concentrations are abolished by pretreatment with a monoclonal anti-CRF antibody (544). Furthermore, the substantial plasma corticosterone response to Poly I:C observed in normal mice is completely absent in mice deficient in IL-6 (716), indicating that Poly I:C-induced activation of the HPA axis is dependent on the elaboration of the cytokine IL-6. / 9j0c$$oc11 P13-8 11-25-98 11:16:36 pra APS-Phys Rev Downloaded from on April 23, 2014 derlying the neuroendocrine responses to bacterial infection and sepsis (214, 863, 883). Although mice and rats are relatively insensitive to LPS in comparison with many other species (including humans), the intravenous administration of LPS to laboratory rodents produces marked elevations in ACTH and corticosterone secretion within 30–60 min. It should be emphasized that, quantitatively, physiological responses to LPS can differ depending on its source and preparation (345). We find that doses of Ç5 mg/kg LPS (Escherichia coli serotype O26:B6; lot 20H4025, Sigma Chemical) produce a peak elevation in plasma ACTH concentration of 500–1,000 pg/ml (compared with õ20 pg/ml in controls) at 90–120 min after intravenous injection in intact, male 3. Murine cytomegalovirus rats (889). Similarly, LPS stimulates ACTH and corticosterone secretion in mice, and HPA activation can be obCytomegaloviruses (CMV) are herpes viruses that are served in both rats and mice after either intravenous or a major cause of mortality and morbidity in human transintraperitoneal administration. However, the precise plant recipients, are a serious problem in patients with mechanisms through which these two routes of LPS adAIDS, and are the most frequent viral cause of congenital ministration influence the HPA axis may be substantially abnormalities. Administration of murine CMV (MCMV) different (144, 925). productively infects mice. Recent studies by Ruzek et al. In addition to elevated blood levels of ACTH and corti(716) showed that MCMV induces increased levels of ILcosterone, other indexes of HPA activation have been re12, IFN-g, TNF-a, IL-1a, and IL-6, but not IL-1b, in the ported after peripheral administration of LPS. Intravenous general circulation at 24–48 h of infection. During this or intraperitoneal LPS produces increased pPVN expression period, there are marked increases in the plasma concenof c-fos mRNA or Fos protein and of CRF hnRNA or mRNA trations of corticosterone and smaller, but statistically sig(230, 387, 456, 680, 718, 924, 925). Rats in which the PVN nificant, increases in plasma ACTH (716). The corticostehas been electrolytically lesioned can mount a detectable rone response to MCMV in either normal mice treated plasma ACTH response to an extremely large dose of LPS (2 with neutralizing anti-IFN-g antibodies, or in IFN-g-defimg/kg ip), but its magnitude is markedly diminished (227), cient mice, is comparable to that in control mice infected indicating that the PVN plays a pivotal role in LPS-stimuwith MCMV (716). However, IL-1 and IL-6 appear to play lated increases in plasma ACTH. Indeed, it is clear that CRF important roles in the activation of the HPA axis. The is an important mediator of LPS-induced ACTH secretion. corticosterone response to MCMV is markedly blunted in This is evidenced by the increased secretion of CRF from either normal mice treated with IL-1ra or in IL-6-deficient the ME after systemic treatment with LPS (292) and by mice, without either of these ‘‘treatments’’ having a sigthe marked attenuation, or abolition, of LPS-induced ACTH nificant impact on viral load. The elevated IL-6 levels prosecretion produced by doses of LPS that are either very duced by MCMV infection are dramatically reduced when large (2.5 mg/kg ip) or more moderate (2.5 mg/kg ip or 50 mice are treated with IL-1ra, whereas IL-1a levels are mg/kg iv), respectively (25, 750). normally elevated in IL-6-deficient MCMV mice (716). ConThese actions of LPS on the HPA axis in vivo are sequently, the authors concluded that IL-6 is the pivotal not due to a direct pharmacological interaction of LPS cytokine in the activation of the HPA axis in response to with HPA axis tissues. Lipopolysaccharide has either no MCMV and that IL-1a plays a secondary role by contributeffect or an inhibitory action on either CRF secretion ing to IL-6 production (716). from hypothalamic explants (545, 581, 652) or ACTH secretion from rat anterior pituitary cell cultures (117, 886). B. Endotoxin Treatment It also seems unlikely that LPS enhances the pituitary ACTH response to CRF, since LPS reduces the expresEndotoxins are LPS constituents of the outermost sion of CRF receptors in the pituitary both in vivo and part of a Gram-negative bacterial cell membrane that are in vitro (25), and ACTH secretion by rat anterior pituitary released upon bacterial lysis. Administration of purified cell cultures stimulated with CRF is unaffected by copreparations of LPS mimics many of the acute phase re- treatment with LPS (886). Furthermore, mice (C3H/HeJ sponses to Gram-negative infection without actively in- strain) that are deficient in their production of IL-1 in fecting the host (123). Consequently, administration of response to LPS (373, 759, 856) exhibit markedly reduced bacterial endotoxins to laboratory animals has been the elevations in the plasma concentrations of ACTH and most commonly used model to study the mechanisms un- corticosterone after intraperitoneal LPS (216), sug- January 1999 REGULATION OF HPA AXIS BY CYTOKINES 15 / 9j0c$$oc11 P13-8 11-25-98 11:16:36 pra APS-Phys Rev Downloaded from on April 23, 2014 gesting that IL-1 is an important mediator of the effects or IL-1ra injected into rats (223, 752) reduce the ACTH of LPS. Lipopolysaccharide is a potent inducer of the response to LPS admistered intravenously or intraperitosynthesis and secretion of a number of cytokines (see neally. A CNS site of IL-1 action has been suggested by sect. IC). In particular, the cytokines IL-1, IL-6, and experiments showing that intracerebroventricular infuTNF-a are likely candidate mediators of the effects of sion of IL-1ra inhibits the increase in CRF mRNA in the LPS on neuroendocrine secretion (863). PVN of rats 8 h after intraperitoneal LPS (387). After administration of LPS directly into the bloodAlthough the above findings seem to strongly implistream, the plasma concentrations of each of these three cate the cytokine IL-1 as a mediator of the activation of cytokines are elevated in a regulated temporal manner the HPA axis by LPS, not all studies support this hypothewith TNF-a first, then IL-1b, and finally IL-6 (174, 189, sis. For example, mice injected with IL-1ra ip, at a dose 290). Not only are the secretions of these three cytokines that inhibited the corticosterone response to either IL-1a temporally related, but there is also evidence that they or IL-1b, failed to inhibit the corticosterone response to are also causally related. Administration of antibodies to LPS (213). Furthermore, the development of genetically TNF-a blunts the secretion of IL-1 and IL-6 in response manipulated mice, with deficiencies in various compoto LPS (263), whereas immunoneutralization of IL-1 (487) nents of the IL-1 system, has raised interesting questions or frequent administration of large doses of IL-1ra (494) regarding the absolute requirement of IL-1 in acute phase abrogates LPS-induced IL-6 secretion. After local injection responses to LPS. For example, fever in response to LPS of LPS (e.g., intraperitoneally or into an experimentally is inhibited by either anti-IL-1b antibodies (418, 461, 487) constructed, subcutaneous air pouch), the local concen- or by IL-1ra (494, 791), clearly implicating IL-1 in the trations of all three cytokines are also elevated. However, pathogenesis of fever due to LPS. However, mice deficient their levels in blood appear to be dependent on the degree in IL-1b show only a slightly decreased (10) or even an of ‘‘overspill’’ into the general circulation, with only IL-6 increased (438) fever in response to intraperitoneal LPS. levels being consistently increased in systemic blood (541, Similarly, although IL-1b has been implicated in the induc542, 844, 998). Local administration of IL-1ra at the site tion of IL-6 and the cachexia after LPS, neither of these of LPS injection inhibits the rise in plasma IL-6 levels responses are inhibited in IL-1b-deficient mice (10, 247, (541), again suggesting a causal relationship between the 250, 438, 1001). Studies in IL-1R1-deficient mice demonproduction of IL-1 and IL-6 after LPS. In light of these strated that IL-1R1 is essential for all the IL-1 mediated data, it is surprising that recent experiments performed signaling events examined (fever, induction of IL-6, inducin mice have shown that the plasma IL-6 response to LPS tion of E-selectin) (442), but these animals display normal appears normal in mutant mice lacking either IL-1b (10, fever and cachexia induced by intraperitoneal LPS (442, 1001) or IL-1R1 (463). Whether this indicates important 463). Not surprisingly, therefore, investigations of the roles for IL-1a (or IL-1g) and the IL-1R2 (or novel IL-1 HPA axis response to LPS in these mutant mice have also receptors) clearly warrants investigation. failed to confirm a role of IL-1 in the elaboration of this Comparisons of the time courses of cytokine produc- HPA axis response (10, 247, 250). tion and HPA axis activation produced by systemic LPS Investigations of the effect of immunoneutralizing ILhave produced somewhat conflicting data. The concentra- 6 and TNF-a have also suggested physiological roles for tions of TNF-a, IL-1b, and IL-6 in plasma have been re- these cytokines in the HPA axis secretory response to ported to lag behind the rise in plasma ACTH after intra- LPS. Although inhibition of either IL-1, IL-6, or TNF-a arterial LPS regardless of LPS dose (290). However, after abrogates the ACTH response to larger doses of LPS in low doses of LPS administered intravenously, elevations mice, Perlstein et al. (640) found that only anti-IL-6 antiin plasma TNF-a coincide with the secretion of ACTH, bodies were completely effective at reducing plasma whereas at higher doses, elevations in plasma TNF-a oc- ACTH concentrations produced by lower doses in mice. cur after the initial rise in plasma ACTH (223). We find In contrast, IL-6-deficient mice show a normal plasma corthat after LPS (5 mg/kg iv), the TNF-a profile in blood ticosterone response to a high dose (1 mg/kg ip) of LPS precedes that of ACTH, with a time of onset and peak (254). In rats, anti-TNF-a antisera inhibits the plasma that occurs 15 min before those of plasma ACTH (889). ACTH response to both low and high doses of intravenous The importance of cytokines in the ACTH response LPS (223, 889), whereas TNF-R1-deficient mice display a to LPS was first directly indicated by the pronounced inhi- normal corticosterone response to intracerebroventricubition of this response when mice were pretreated with lar LPS (2.5 mg). IL-1 receptor antibodies (690). Further studies showed From the above discussion, it is apparent that the that destruction of macrophages produced a marked re- precise role played by IL-1, IL-6, and TNF-a in the elaboraduction in circulating IL-1 levels in response to a high tion of the HPA axis response to LPS is not fully underdose of LPS (2.5 mg/kg iv) and a 40% inhibition of the stood. That each of these three cytokines affects the synACTH response to a small dose of LPS (2.5 mg/kg iv) (195). thesis and secretion of the other, that each is capable of Either anti-IL-1 receptor antibodies given to mice (640) enhancing the others’ effect in a synergistic manner, and 16 ANDREW V. TURNBULL AND CATHERINE L. RIVIER Volume 79 the possible redundancy of each of these cytokines undoubtedly contribute to the lack of clarity of the various studies described. Overall, however, the evidence presented seems to indicate that, depending on experimental paradigm, one or more of IL-1, IL-6, and/or TNF-a may contribute to the HPA axis secretory response to LPS. C. Local Inflammation / 9j0c$$oc11 P13-8 FIG. 2. Plasma concentrations of ACTH, corticosterone, and interleukin-6 (IL-6) in rats after (intramuscular) injection of 50 ml/100 g body wt of either saline (s) or turpentine (j). Thick, broken bar represents dark cycle (lights out). [From Turnbull and Rivier (884); q The Endocrine Society.] IL-6 response to turpentine is completely absent in either of these mutants (463, 1001). Interestingly, however, ICEdeficient mice fail to generate mature IL-1b in response to LPS (469) but exhibit normal production of mature IL-1b and display normal plasma IL-6 responses, when injected with turpentine (248). These latter studies clearly indicate that distinct molecular mechanisms of IL-1b and IL-6 elaboration are operative during systemic (LPS) and local (turpentine) inflammation. Interleukin-6 has been demonstrated to be an obligatory mediator of a number of acute phase responses to local inflammation induced by turpentine, including fever, cachexia, and increased hepatic protein synthesis (87, 247, 254, 432, 437, 603). Because IL-6 is the only identified cytokine in the systemic circulation in significant quantities after turpentine, it seems likely that it is the major circulating signal to the brain. Nevertheless, there is only 11-25-98 11:16:36 pra APS-Phys Rev Downloaded from on April 23, 2014 A number of studies have investigated the mechanisms by which acute local inflammation produces activation of the HPA axis (169, 879, 881, 884, 965). One muchstudied model consists of the subcutaneous or intramuscular injection of the irritant turpentine into the mouse or rat. Injection of turpentine produces a localized inflammation that is characterized by a centrally necrotic, well-defined abscess and increased vascular permeability (476, 620, 829, 978). This paradigm has been used to investigate a multitude of acute phase responses to local inflammation including fever, hypermetabolism, cytokine synthesis and secretion, protein metabolism, anorexia, neuroendocrine alterations, and hepatic acute phase protein synthesis (27, 167–169, 247, 286, 432, 603, 965, 978, 1001). The intramuscular injection of turpentine produces a biphasic activation of the HPA axis in the rat (see Fig. 2). Increased ACTH secretion shortly after turpentine administration appears to be due to activation of nociceptive sensory afferents (879) and is not related to cytokine synthesis or secretion (247, 254). By 3 h after turpentine, plasma ACTH concentrations return temporarily to around those of control animals (Fig. 2). This is followed by a second rise in plasma ACTH and corticosterone concentrations that parallels the development of the local inflammation, lasts for Ç24 h, and is the HPA axis response to the actual local inflammation per se (884). Turpentine-induced inflammation produces a long-lasting (at least 12 h) increase in the expression of Fos in the PVN (696), and the second rise in plasma ACTH concentration is completely reversed by the administration of anti-CRF antiserum (884), indicating the importance of hypothalamic CRF secretion to the plasma ACTH response. The generation and role of cytokines during acute phase responses produced by turpentine injection has been well studied. Turpentine-induced local inflammation elicits a marked elevation in the plasma levels of IL-6, but not of IL-1 or TNF-a (167, 248, 495, 881). However, concentrations of IL-1 are elevated at the site of local inflammation induced by turpentine (248), and inhibition of either TNF-a (167) or IL-1 (286, 495, 879) action markedly reduces the levels of IL-6 in blood, suggesting that both these cytokines stimulate the secretion of IL-6 at the local inflammatory site. Although IL-1b or IL-1R1-deficient mice display normal IL-6 responses to LPS, the plasma January 1999 REGULATION OF HPA AXIS BY CYTOKINES D. Physical and Psychological Stress The elaboration of cytokines appears not to be restricted to injurious, inflammatory, and infectious insults, / 9j0c$$oc11 P13-8 FIG. 3. Effects of turpentine-induced local inflammation on plasma corticosterone in either wild-type (IL-6 ///) or IL-6-deficient (IL-6 0/ 0) male mice. Plasma samples were collected at 9 h after either saline or turpentine administration. *** P õ 0.002. (From A. V. Turnbull, S. J. Hopkins, S. Prehar, and C. L. Rivier, unpublished data.) since recent studies have indicated that IL-1, IL-6, and brain-derived neurotrophic factor (BDNF) synthesis and/ or secretion are altered during acute physical or psychological stresses (462, 536, 546, 777, 778, 797, 1002). For example, plasma IL-6 levels are elevated in rats by exposure to a novel environment (462, 561), conditioned aversive stimuli (1002), electroshock (883, 1002), or restraint (1002). Furthermore, IL-6 mRNA is elevated in the midbrain and IL-6R mRNA is diminished in the midbrain and hypothalamus 4–24 h after restraint stress in the rat (779), whereas immobilization causes increases plasma IL-6 concentrations and elevated hepatic and splenic IL-6 mRNA expression in mice (417). In humans, plasma IL-6 levels increase rapidly after treadmill exercise with peak increases apparent at 15 and 45 min (622). The increases in plasma IL-6 after physical and/or psychological stresses in rats are much more rapid (within 15 min) than those observed after either local (turpentine, 2–3 h) or systemic (LPS, 45–60 min) inflammations and appear to be mediated by an action of catecholamines (196, 800, 852, 910). However, increased blood levels of IL-6 do not appear to directly contribute to the HPA axis response to acute stress, since the rise in plasma IL-6 levels is only modest, and although plasma IL-6 levels increase rapidly, they still lag behind plasma ACTH responses (883, 1002). Furthermore, Ruzek et al. (716) reported that IL-6-deficient mice display an increase in plasma corticosterone levels in response to restraint stress that is comparable to that found in wild-type mice. Acute restraint or immobilization has also been reported to increase hypothalamic IL-1b mRNA (546, 828), IL-1 protein (778), and IL-1RA mRNA (828) within 30 min of commencement of stress. In addition, chronic physical/ psychological stress elevates both plasma IL-1b concentrations in rats (536) and humans (814) and hypothalamic 11-25-98 11:16:36 pra APS-Phys Rev Downloaded from on April 23, 2014 limited evidence indicating that IL-6 mediates the HPA axis response to turpentine. Plasma IL-6 concentrations correlate well with the second rise in plasma ACTH and corticosterone levels (879, 884) (see Fig. 2), which given the known stimulatory effects of IL-6 on HPA axis secretory activity (327, 499, 519, 520, 527, 574, 575, 809) suggests that IL-6 is a likely circulating mediator of this neuroendocrine response to turpentine (879, 884). However, one report shows that immunoneutralization of systemic IL-6 does not influence the rise in plasma corticosterone in mice 12 h after turpentine (603). It should be noted that in this study (603), administration of IL-6 antibodies resulted in enhanced rather than diminished biological activity of IL-6 in plasma, a finding that has been commonly reported (reviewed in Ref. 760), and which casts doubt on the significance of the lack of effect on plasma corticosterone levels in response to turpentine. Studies in both IL-1b- and IL-6-deficient mice have shown that neither IL-1b nor IL-6 is an obligatory mediator of the elevation in plasma corticosterone concentrations shortly (1.5– 2 h) after turpentine (247, 254). However, the time point chosen for investigation by these authors corresponds to the initial, pain-related increase in HPA axis secretory activity (see Fig. 2), and no observation was made at later time points corresponding to the HPA axis response to the actual local inflammatory reaction (6–24 h). We have recently obtained evidence that indicates that IL-6 is an important mediator of the HPA axis response to local inflammation (A. V. Turnbull, S. J. Hopkins, S. Prehar, and C. L. Rivier, unpublished data). At 9–12 h after turpentine, when plasma IL-6 levels are maximally elevated in control animals (see Fig. 2), IL-6-deficient mice display a very markedly reduced (two-thirds inhibited) plasma corticosterone response (Fig. 3). These data together with those demonstrating reduced fever (437), acute phase protein synthesis (432), and cachexia (432, 437) in IL-6-deficient mice collectively indicate that IL-6 is an important circulating mediator during local inflammation, acting as an ‘‘SOS’’ signal and inducing a variety of acute phase responses. There is also evidence for the involvement of other cytokines in this response. Although intramuscular turpentine in rats appears not to elevate mRNA for either IL1b, IL-6, or TNF-a within the CNS or pituitary, intracerebroventricular administration of either a neutralizing antiTNF-a antiserum or a dimeric soluble TNF-a receptor construct markedly inhibits ACTH secretion 6–9 h after turpentine in the rat (881). This indicates an important, although as yet unexplained, role of cerebral TNF-a in this response. The extent to which other CNS-derived cytokines may contribute to the enhanced secretory activity of the HPA axis is presently unknown. 17 18 ANDREW V. TURNBULL AND CATHERINE L. RIVIER E. Basal Hypothalamic-Pituitary-Adrenal Activity Perhaps even more surprising than the demonstrated role of cytokines in the regulation of the HPA axis in response to noninflammatory or noninfectious stress is the recent finding that the cytokine LIF may contribute to the regulation of HPA axis secretion under basal, nonstress conditions. Although inhibition or genetic deletion of IL-1, IL-6, or TNF-a does not significantly affect basal plasma ACTH or corticosterone concentrations, recent studies by Melmed and colleagues (6, 7, 667, 926) have demonstrated that a member of the gp130 signaling family of cytokines, LIF, plays an important role in the regulation of basal ACTH secretion. Either normal or 36-h fasted mutant LIF-deficient mice have lower basal plasma concentrations of ACTH than wild-type controls, an effect that can be reversed / 9j0c$$oc11 P13-8 by administration of exogenous LIF (6). This suggests that either LIF is important in the development and maturation of the HPA axis or that it represents a tonic ACTH secretagogue in the adult animal. IV. CYTOKINE ACTIONS ON THE CENTRAL NERVOUS SYSTEM, PITUITARY, AND ADRENAL The effects of both administration of cytokines to normal, healthy subjects and the consequences of inhibiting cytokine action during infectious, inflammatory, or stressful threats imply that cytokines may play a physiological role in the regulation of the secretory activity of the HPA axis. However, cytokines also produce a number of systemic acute phase responses that themselves could elicit HPA activation, raising the question of whether the effects of cytokines on HPA axis secretory activity are direct or secondary to stress produced by other acute phase responses. For example, IL-1b causes fever, sickness behavior, increases in heart rate, increased blood flow to certain vascular beds, activation of the sympathetic nervous system, and changes in intermediary metabolism. These physiological changes are themselves challenges to the maintenance of homeostasis, and each could, if pronounced, activate secretion by the HPA axis. The effects of some cytokines on plasma ACTH concentrations have nevertheless been dissociated from a number of these other acute phase responses. For example, in the original account by Besedovsky et al. (70), IL-1 induced activation of the HPA axis of mice kept at an ambient temperature that did not result in these animals mounting a febrile response. Indeed, IL-1b analogs with markedly reduced pyrogenicity still stimulate ACTH secretion (572). In addition, enhanced ACTH secretion is observed after peripheral administration of IL-1b at doses of IL-1b that have no, or only modest, effects on the secretion of other hormones, such as luteinizing hormone, catecholamines, and prolactin, whose secretion is markedly altered by many other types of stressors (399, 695, 886). Similarly, doses of IL-6 that markedly elevate plasma ACTH and cortisol concentrations in humans have only moderate effects on other acute phase responses (519, 520). Finally, studies described in section IIIE clearly indicate that regulation of ACTH secretion by LIF can be demonstrated in healthy animals. These findings suggest cytokines target the HPA axis in a specific manner. The original Science papers of 1987 suggested that the influence of IL-1 on pituitary ACTH secretion was attributable to actions either at the level of hypothalamic CRF release (55, 730) or directly on the pituitary itself (62) to stimulate ACTH secretion. Furthermore, although original hypotheses regarding a lymphoid-adrenal axis whereby ACTH produced by lymphocytes represented the 11-25-98 11:16:36 pra APS-Phys Rev Downloaded from on April 23, 2014 IL-1b mRNA in mice (837). On the basis of studies showing that intrahypothalamic administration of IL-1ra produces a significant reduction of the plasma ACTH response to immobilization in rats, a role for IL-1 in the regulation of the HPA axis response to a stress unrelated to infection or inflammation has now been proposed (777, 778). Indeed, other studies have shown that intracerebroventricular administration of IL-1ra before inescapable shock blocks the subsequent interference with escape learning and enhancement of fear conditioning normally produced by such a stressor (511), suggesting that IL-1 may also mediate some behavioral effects of noninflammatory/infectious stresses. The findings that cytokines may be elaborated quickly (within minutes) in response to a stimulus that does not appear to result in tissue damage or infection is novel and suggests a role of cytokines in homeostasis that has previously been unrecognized. It should be pointed out that many of the physiological responses to inflammatory/ infectious stressors and psychological/physical stressors are common (e.g., activation of the HPA axis, suppression of reproduction, certain changes in behavior, fever, and reduced appetite). Indeed, psychological/physical stress produces many aspects of the acute phase response to sickness. Furthermore, although humans experience psychological/physical stress commonly without the presence of inflammatory/infectious stress, psychological/ physical stress commonly precedes inflammatory/infectious stress in animals in the wild (e.g., predator-prey experiences, shortage of food/water supply). That the rapid elaboration of cytokines may contribute to the signal-generating physiological (e.g., neuroendocrine) responses to psychological/physical stressors (778) suggests that, mechanistically, responses to such stressors may not differ markedly from responses to inflammatory/ infectious stressors. Volume 79 January 1999 REGULATION OF HPA AXIS BY CYTOKINES A. Evidence That Cytokines Activate the Hypothalamic-Pituitary-Adrenal Axis Primarily at the Level of the Central Nervous System 1. Cytokine receptors within the CNS Receptors to many cytokines have been localized within the CNS or described in primary cell cultures or cell lines derived from brain tissue. These include receptors for IL-1, IL-2, IL-3, IL-4, IL-6, IL-7, interferons, TNF, growth factor, CSF, growth factors, and neurotrophins (for reviews, see Refs. 65, 344, 762) (Table 6). Of most relevance to this review article is the distribution throughout the rodent CNS of the receptors for the cytokines IL- / 9j0c$$oc11 P13-8 1, IL-6, and TNF-a, and these are discussed in more detail here. A) IL-1 RECEPTORS IN THE CNS. Early studies investigating the localization of IL-1 receptors in the brain indicated a fairly widespread distribution. High levels of specific binding of 125I-labeled IL-1b were found in the choroid plexus, dentate gyrus, hippocampus, cerebellum, and olfactory bulb, with low levels in the hypothalamus and ME in rat brain slices (251). Specific binding of 125I-labeled IL1b to membrane preparations of rat hypothalamus and cortex were also reported (398). Subsequent studies have confirmed the existence of IL-1 receptors within the rodent CNS, and IL-1R1 mRNA or IL-1 binding have been demonstrated on neurons (see below), astrocytes (31, 714, 868), cerebrovascular endothelia (904), neuroblastoma cells (625), and glioblastoma cells (303), but not on microglia (31, 868). However, the localization within the rat brain appears to differ somewhat from that which was originally reported, in particular with respect to the presence of IL-1 receptors within the hypothalamus. Furthermore, there are marked differences in the distribution of IL-1 receptors in rat and mouse brains. Overall, the mouse brain exhibits very low densities of IL-1 receptors as assessed by binding of 125I-labeled IL1a, IL-1b, or IL-1ra. However, very high levels of labeling are found consistently in the hippocampus (dentate gyrus, but not CA1 to CA4 pyramidal regions), choroid plexus, and meninges (30, 841, 848). Within the dentate gyrus, IL1 binding appears to be predominantly to neurons (30, 848). Most notably, none of the more recent studies reported substantial IL-1 binding in the hypothalamus (30, 841, 848). In situ hybridization histochemical analyses of mouse brains have indicated that IL-1R1 mRNA is expressed predominantly in the granule cell layer of the dentate gyrus, the entire midline raphe system, the choroid plexus, and endothelial cells, but not in the hypothalamus (177, 178). In contrast, IL-1R2 mRNA has been undetectable in normal mouse brain using in situ hybridization histochemical procedures (202). As in the mouse, the rat choroid plexus, but not hypothalamus, shows significant IL-1 binding (516, 845, 848). However, in marked contrast to the robust IL-1 binding in the mouse hippocampus, the rat hippocampus displays no binding of either IL-1a, IL-1b, or IL-1ra (using either heterologous or homologous ligands) (516, 845, 848). Similarly, in situ hybridization signal for IL-1R1 mRNA over the rat hippocampus has been described as either weak (972, 982) or background (238), with no study demonstrating significant signal in the dentate gyrus. The IL-1R1 mRNA in rat brain is confined largely to nonneuronal cells, with the ependymal cells lining the ventricular system, the choroid plexus, the leptomeninges, and in particular endothelial/perivascular cells being the major sites of IL1 receptor expression (178, 238, 969, 970, 972, 982). A few neuronal groups in the rat brain do, however, display low 11-25-98 11:16:36 pra APS-Phys Rev Downloaded from on April 23, 2014 link between activation of the immune system and adrenal hormone secretion (793) has fallen out of favor, other studies (e.g., Ref. 698) suggest that cytokines may act on the adrenal directly. The following sections describe the evidence that indicates the potential site(s) of cytokine action on HPA axis secretory activity. In presenting arguments for each level of the HPA axis (CNS, pituitary, and adrenal), we consider three lines of evidence. First, we describe the localization of cytokine receptors within the HPA axis. The a priori condition for a particular cytokine to influence HPA axis secretory activity by an action at a particular level is the expression of functional receptors for that cytokine by the tissue under consideration (e.g., hypothalamus) or at least in functionally related tissues (e.g., other regions of the CNS which send projections to the hypothalamus). Second, we describe the expression of cytokines by tissues of the HPA axis. It was originally hypothesized that the influence on neuroendocrine function of endogenous cytokines resulted from the exposure of the CNS and pituitary to cytokines produced by circulating or tissue-resident cells such as macrophages, monocytes, fibroblasts, and B and T lymphocytes. However, studies over the last decade have demonstrated that many IL, chemokines, TNF, IFN, CSF, and growth factors are produced by numerous cell types, including those found within neuroendocrine systems. Therefore, it appears that cytokines may play a paracrine or autocrine role in the regulation on neuroendocrine function, as they do in the immune system. In general, levels of cytokines in resting, healthy, unstressed animals or humans are low, but the expression of a number of cytokines can increase dramatically during injury, infection, disease, or physical/psychological stress. The following sections therefore outline what is known about the synthesis of cytokines within the CNS, pituitary, and adrenal and how this expression may be regulated. Finally, we discuss the numerous in vivo and in vitro studies that have investigated the effects of cytokines on each component of the HPA axis. 19 20 ANDREW V. TURNBULL AND CATHERINE L. RIVIER TABLE Volume 79 6. Cytokines and their receptors in the CNS Cytokine IL-1a IL-1b IL-1ra IL-2 IL-3 IL-4 IL-5 IL-6 IL-7 IL-8 IL-10 IL-11 IL-12 IL-13 IL-15 MIP-1b LIF CNTF TNF-a TNF-b MIF IFN-a IFN-b IFN-g IGF-I IGF-II NGF EGF bFGF TGF-a TGF-b Activin G-CSF M-CSF GM-CSF SCF Neurotrophins (NGF, BDNF, NT-3) / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / Induced by Systemic LPS Receptor Reference No. / / //0 / / / / / / / / / //0 / 30, 178, 238, 277, 672 30, 101, 124, 178, 238, 277, 453, 454, 644, 901, 902 269, 277, 353, 472, 841, 971 18, 448 16, 252, 430 407, 490, 977 736 273, 274, 277, 453, 644, 746, 748, 749, 900, 988 538 473, 721, 834, 979 349, 971 210 624 971 316, 460 547 926, 987 208, 823 102, 277, 414, 453, 644, 967 559 590 99, 364, 834, 983, 984 834 403, 484, 644, 834 4, 43, 93, 391, 465, 515, 704, 723, 956 93, 391, 465, 533, 704, 723 32, 240, 288, 425, 670, 811 245, 259, 504 228, 360, 486 259, 502, 503, 960 486, 646 136, 697 12, 593, 834 8, 12, 154, 266, 595, 663, 834 12, 513, 593, 663, 834 313, 411, 514, 706, 834, 973, 1000 38, 125, 184, 185, 475, 797, 798 / 0 / / / / / / / / / / / / / / / / / / / / / / / / Definitions are as in Table 3. Reference numbers with regard to IL-8 include the homologous cytokines cinc/gro/NAP-1. to moderate levels of IL-1R1 mRNA: the basolateral nucleus of the amygdala, the arcuate nucleus of the hypothalamus, the trigeminal and hypoglossal motor nuclei, and the area postrema (238). As in the mouse, IL-1R2 mRNA is undetectable in the rat brain by in situ hybridization histohemistry (592), although the expression of IL1R2 mRNA is induced by systemic treatment with kainic acid (592). The low levels of IL-1R1 mRNA observed in the hippocampal formation of the rat are in apparent contrast to the localization in the rat of IL-1RAcP. The IL-1RAcP mRNA is highly expressed in both mouse (304) and rat brain (482). In situ hybridization studies of rat brains demonstrated that in contrast to IL-1R1 mRNA, IL-1RAcP mRNA is highly expressed in the granule cell layer of dentate gyrus, a region in which IL-1R1 mRNA is expressed in mice but not in rats (482). Furthermore, IL1R1 and IL-1RAcP mRNA are differentially regulated by peripheral LPS treatment (271, 353). It therefore seems / 9j0c$$oc11 P13-8 possible that the IL-1RAcP in the brain may also serve as an accessory protein to novel IL-1 receptor(s) or has functions unrelated to IL-1 receptor signaling. In addition to the radioligand binding and in situ hybridization studies described above, RNase protection assay (RPA) (238, 280, 352, 353) and RT-PCR (270, 625) procedures have been used fairly extensively to investigate the distribution and regulation of IL-1R1 and IL-1R2 mRNA in both rat and mouse brain. Parnet et al. (625) found transcripts for both IL-1R1 and IL-1R2 in whole mouse brain but showed that the murine neuroblastoma cell line C1300 expresses only IL-1R1 mRNA. Indeed, Gabellec et al. (270) also demonstrated transcripts for both IL-1 receptors in the mouse brain but found that IL-1R1 mRNA was the predominant species in brain, whereas IL1R2 mRNA was the most abundant in the spleen. Although previous work showed that systemic LPS reduces IL-1 binding in rat and mouse brain (29, 321, 517, 840, 842, 843), RT-PCR and RPA analyses have shown that either 11-25-98 11:16:36 pra APS-Phys Rev Downloaded from on April 23, 2014 Cytokine January 1999 REGULATION OF HPA AXIS BY CYTOKINES / 9j0c$$oc11 P13-8 include the hypothalamus and, of particular interest, the PVN (900). Gp130 mRNA is also expressed by cerebrovascular elements of LPS-treated rats (900). C) TNF RECEPTORS IN THE CNS. Currently, there is little known of the distribution or physiological role of either TNF receptor within the CNS. Studies utilizing radioligand binding of 125I-rmTNF-a to sections of whole mouse brain have demonstrated only weak specific binding throughout the entire surface of brain tissue (967), and binding assays of tissue homogenates have shown specific binding in the mouse brain stem, cortex, thalamus, basal ganglia, and cerebellum (414). In vitro studies have shown that both TNF-R1 and TNF-R2 mRNA are present in mouse cerebrovascular endothelium (49). In microglia, astrocytes, and oligodendrocytes, both TNF-R1 and TNF-R2 can be expressed in humans (788, 823a, 834, 963), whereas at least one receptor subtype is present in rats and mice (17, 209, 855). Both undifferentiated and differentiated clonal murine neuroblastoma cells (N1E cells) express TNF-R1, but not TNF-R2, mRNA (787). The TNF-R1 immunoreactivity has also been demonstrated in neurons in the substantia nigra of humans and both TNF-R1 and TNF-R2 immunoreactivities shown in human hippocampal and striatal neurons (92). However, there is presently no evidence that either TNF-a receptor subtype is localized to hypothalamic regions directly involved in the regulation of HPA axis secretory activity. 2. Cytokine expression in the CNS The production and actions of cytokines within the CNS have been reviewed extensively in a number of recent excellent review articles (65, 344, 710, 711, 745, 762), and only a brief overview pertinent to the discussion of cytokine influence on the HPA axis is given here. A) BASAL EXPRESSION. Many cytokines are synthesized within the brain (see Table 6), although in most cases their expression in healthy, stress-free subjects is low. Nonetheless, a number of studies have reported the distributions of IL-1, IL-6, and TNF-a immunoreactive or biologically active protein or mRNA in the brains from normal untreated subjects. In the human brain, IL-1b immunoreactivity is found within neuronal elements of the hypothalamus, including periventricular regions, the pPVN, and the ME (101). This distribution is consistent with a role of IL-1b as a neuroregulator of acute phase responses, and in particular, of the HPA axis (101). Although studies in rats also detected neuronal immunoreactive IL-1b in similar hypothalamic regions, more prominent staining was found in extrahypothalamic sites, particularly the hippocampus (454). Interleukin-1b immunoreactivity has also been reported in the rat hypothalamus (672). Interleukin-1 biological activity in the rat brain has been either undetectable (264, 655) or detected in brain stem, cerebral cortex, diencephalon, and hippocampal homogenates (32, 11-25-98 11:16:36 pra APS-Phys Rev Downloaded from on April 23, 2014 LPS or IL-1b increases the expression of IL-1R1 and IL1R2 mRNA (270, 271, 281, 353, 354, 357, 646, 668). These differences between binding studies and mRNA analyses presumably relate to either increased receptor occupancy after LPS treatment (see sect. IVA2B) or decreased translation of receptor mRNA into receptor protein. B) IL-6 RECEPTORS IN THE CNS. Specific IL-6 binding sites have been demonstrated in both astrocytoma and glioblastoma cell lines (835), as well as in extracts of bovine hypothalamus (170). Messenger RNA encoding the a-subunit of the IL-6 receptor (IL-6Ra) has also been detected in neurons, microglia, and astrocytes from either normal brain tissue, primary cell cultures, or tumor cell lines (735, 834). The IL-6Ra mRNA is expressed in several brain regions in the untreated rat (273, 274, 746, 749, 900, 988). The IL-6Ra mRNA is most abundant in the pyrimadal cells of the CA1 and CA4 regions of the hippocampus and in the granule cell layer of the dentate gyrus (900) and has also been detected in the hypothalamus, cerebellum, hippocampus, striatum, neocortex, and pons/medulla (273, 274, 746, 749, 988). Specific hybridization signals are observed in glial cells of the lateral olfactory tract, in ependymal cells of the olfactory and anterior lateral ventricle, and in neurons of the piriform cortex, medial habenular nucleus, neocortex, hippocampus, and hypothalamus (746). Within the hypothalamus, IL-6Ra mRNA is present in the ventromedial and dorsomedial regions including the periventricular hypothalamus and in the medial preoptic nucleus. However, the anterior hypothalamus and PVN display no specific hybridization signal for IL-6Ra mRNA (746). The expression of IL-6Ra mRNA in the rat brain appears to be developmentally regulated, with marked increases in its expression, particularly in the striatum, hypothalamus, hippocampus, and neocortex, between 2 and 20 days of age (273, 274). Furthermore, LPS administration markedly elevates IL-6Ra mRNA levels in several rat brain regions (area postrema, bed nucleus of the stria terminalis, amygdala, cerebral cortex, claustrum, hippocampus, ME, piriform cortex, septohippocampal nucleus, PVN, SFO, and OVLT) (900). Furthermore LPS (intraperitoneal) or IL-1b (intravenous) stimulates the expression of IL-6Ra mRNA over blood vessels throughout the brain (900). In addition to IL-6Ra, the signal-transducing component of the IL-6 receptor, gp130, has also been localized within the rat CNS (900, 927). Gp130 is found in glial, neuronal, oligodendrocyte, and ependymal cell types. The distribution of immunoreactive gp130 in the rat brain overlaps that which has been observed for IL-6Ra but is more widespread, consistent with its role in signal transduction for other members of the IL-6 family (927). Indeed, gp130 mRNA has been detected throughout the normal rat brain, with positive hybridization signals detectable in almost all brain areas (900). These brain areas 21 22 ANDREW V. TURNBULL AND CATHERINE L. RIVIER / 9j0c$$oc11 P13-8 demonstrated, microglia appear to be the major ‘‘brainresident’’ cell type that synthesizes IL, chemokines, TNF, and IFN, although vascular cells, astrocytes, and neurons also contribute to cytokine production. Of particular significance to the field of immune-nervous system interactions has been the hypothesis that the synthesis of cytokines in brain may be induced by stimuli other than those resulting in direct cellular challenge to the CNS, and consequently that cytokines may act as neuroregulators within the brain in a manner akin to classical neuropeptides. Indeed, in response to the peripheral administration of LPS, the CNS expression of a number of cytokines is elevated (see Table 6). In response to large doses of LPS (0.4–4 mg/kg ip or iv), the mRNA encoding IL-1a, IL-1b, IL-1ra, IL-6, and TNF-a are elevated in homogenates of several regions of the mouse brain as assessed by RT-PCR and Northern blot hybridization methodologies (28, 269, 277, 453, 570). These elevations have been noted within 1 h, and peak at Ç6 h. However, an important question regarding the induction of cytokines in the brain by LPS is whether the stimulus causing increased synthesis is of peripheral origin, because large doses of LPS could, for example, penetrate the BBB in sufficient quantities to stimulate cytokine synthesis directly. Indeed, LPS is a potent stimulus of IL-1, IL-6, and TNF-a synthesis after its intracerebroventricular administration (197, 338, 655, 881) and induces cytokine synthesis by glial cells in cell culture (770). In addition, large doses of LPS may disrupt the BBB (91, 199, 483, 496, 781, 878), thus permitting the entrance from the periphery of cells (e.g., macrophages) that may contribute to the cytokine signal. The majority of RT-PCR studies have been performed using high doses of LPS, and the fact that these have not fully addressed issues regarding contamination with blood cells and possible disruption of the BBB makes conclusions difficult. However, recent studies by Pitossi and co-workers (643, 644) used semi-quantitative RT-PCR to measure cytokine production after the injection of LPS to mice, at a dose (20 mg/kg ip) that is reported not to influence BBB integrity. Importantly, these authors also quantified possible contaminaton by peripheral blood cells. This work showed marked induction of IL-1b, IL-6, TNF-a, and IFN-a mRNA in several brain regions (cortex, cerebellum, thalamus/striatum, hippocampus, brain stem, and hypothalamus), with peak increases observed 2–4 h after LPS administration (644). Because the authors concluded that these increased signals could not be accounted for by contamination with peripheral blood cells, it is clear that these cytokines are induced in brain by doses of LPS that do not disrupt the BBB. A number of in situ hybridization and immunocytochemical studies have investigated the distribution of IL-1b mRNA or IL-1b protein after systemic (iv or ip) LPS in rats and rabbits and have yielded very similar results. ‘‘Barrier-related’’ regions have been the most 11-25-98 11:16:36 pra APS-Phys Rev Downloaded from on April 23, 2014 656, 778). In the normal rat or mouse hypothalamus, IL1b is detectable using sensitive immunoassays (314). However, the majority of in situ hybridization studies have found that the brain parenchyma lacks a readily distinguishable IL-1b mRNA signal (124, 338, 546, 981), whereas constitutive expression of IL-1b in the cerebrovasculature of control animals is readily observable (969, 970). Similarly, the majority of Northern blot hybridization or RTPCR studies have found extremely low or undetectable levels of IL-1a or IL-1b mRNA in the brains of control rats or mice (197, 277, 338, 453, 507, 644), although sufficient sensitivity to demonstrate small diurnal variations in rat brain IL-1b mRNA expression was achieved in one study (838). Messenger RNA of the gene encoding ICE, the enzyme responsible for cleavage of pro-IL-1b to mature, active IL-1b, has been demonstrated in murine microglia (990), whole brain homogenates (401), homogenates of hypothalamus and hippocampus (452, 865, 866), and blood vessels (arterioles and venules) throughout the brain parenchyma (970) of control rats. Interleukin-1 receptor antagonist mRNA is also present within the rat brain (269, 281, 353–357, 472, 485, 970, 971), with positive in situ hybridization signal present in the hypothalamus (particularly the PVN), hippocampus, cerebellum, choroid plexus, and blood vessels throughout the brain (472, 970). Tumor necrosis factor-a immunoreactivity is found in the hypothalamus, caudal raphe nuclei, and along the ventral surface of the brain in the pons and medulla in the normal mouse brain (105). On the basis of morphological observations, the majority of staining observed appears neuronal, with two principal fiber pathways being noted: a periventricular pathway which coursed along the ventricular system and a pathway associated with the medial forebrain bundle (105). Within the hypothalamus, the PVN represents one of the terminal fields of fibers originating from the most intensely stained cell groups within the bed nucleus of the stria terminalis. On the basis of in situ hybridization studies, there is only a weak signal over regions that coincided with immunoreactive TNF-a (105). Finally, IL-6 mRNA has been either undetectable (900) or shown to be colocalized with IL-6Ra mRNA within several regions of the normal rat brain, including hypothalamus, cerebellum, hippocampus, striatum, neocortex, and pons/ medulla (746). B) INDUCED EXPRESSION. The expression of a number of cytokines within the CNS increases dramatically upon cellular damage. Accordingly, local concentrations of IL1b, IL-6, and TNF-a, in particular, are elevated during CNS bacterial or viral infections, brain trauma, cerebral ischemia, and convulsions (344, 745). In addition, their expression is increased during a number of chronic CNS disorders such as multiple sclerosis, Down’s syndrome, and Alzheimer’s disease (344, 745). In general, when induction of cytokine synthesis within the brain has been Volume 79 January 1999 REGULATION OF HPA AXIS BY CYTOKINES / 9j0c$$oc11 P13-8 tine-induced inflammation (Ref. 881 and unpublished observations). Recent studies have suggested that cytokine synthesis in brain may also be induced by stressors unrelated to infection or inflammation. Hypothalamic expression of IL-1b mRNA (546, 828), IL-1ra mRNA (828), and IL-1 bioactivity (778) is increased within 30 min of immobilization stress in the rat, and IL-6 mRNA is elevated in the midbrain 4–24 h after restraint stress (779). Similar paradigms produce increases in IFN-g mRNA expression in mouse brain homogenates (849). Acute (2 h) or repeated immobilization stress in rats increases BDNF mRNA expression in the pPVN and the lateral hypothalamus (797) and decreases BDNF mRNA in the hippocampus, whereas repeated stress increases NT-3, but not NT-4, mRNA in the hippocampus (798). 3. Cytokine actions at the level of the CNS Consistent with the CNS as a primary target of IL-1 action in eliciting pituitary ACTH secretion, administration of either IL-1a or IL-1b directly into the cerebroventricles (intracerebroventricular) of rats markedly elevates plasma ACTH concentrations. Elevation in plasma ACTH concentrations produced by intracerebroventricular IL-1 generally occurs at considerably lower (5- to 20-fold less) doses than those required by intravenous IL-1 (399, 684, 695, 909). Similarly, IL-2, IL-6, TNF-a, and epidermal growth factor (EGF) have been shown to elevate plasma ACTH and/or corticosterone concentrations when administered via the intracerebroventricular route (see Table 5). Interleukin-1 infused directly into several brain sites, including the PVN (40, 939), ME (525–527, 530, 939), and hippocampus (477), also increases pituitary ACTH secretion. The effectiveness of cytokines when administered directly into the brain, and in particular the fact that lower doses are usually required to stimulate HPA axis secretory activity than when administered peripherally, have been interpreted as evidence that the activation of the HPA axis by peripherally administered cytokines occurs via an action within the CNS. This assumption based on such dose-response studies alone is at least questionable, given the differences in dilution of the cytokine when administered via these two routes. Indeed, at least in the cases of IL-1b and TNF-a, activation of the HPA axis is associated with patterns of gene expression within the PVN and/or pharmacological profiles that differ according to whether the cytokine was administered peripherally or centrally (457, 684, 688, 881). This indicates that the mechanisms by which these routes of cytokine administration stimulate HPA axis secretory activity are distinct. However, a number of lines of evidence do suggest that the stimulation of pituitary ACTH and adrenal GC secretion by either centrally or peripherally administered cytokine 11-25-98 11:16:36 pra APS-Phys Rev Downloaded from on April 23, 2014 consistently observed sites of IL-1b expression after systemic LPS (124, 576 – 578, 971). These include the circumventricular organs [CVO; including OVLT, SFO, ME, area postrema (AP), and pineal gland], meninges, and choroid plexus. The cell types expressing IL-1b in these regions include macrophages, microglia, and perivascular cells. Marked induction of IL-1b in microglia throughout the entire brain has also been observed, but this tends to occur only at larger doses of LPS (ú2.5 mg/kg vs. õ1 mg/kg for barrier related) (124, 902, 971). Furthermore, the induction of IL-1b expression in barrier-related regions seems to occur faster (by 1 – 2 h) than that in brain parenchyma (peak Ç6 – 8 h). Immuno- and bioassays have also been used to document increases in brain cytokine concentrations. Lipopolysaccharide administered intraperitoneally increases the immunoreactive concentration of IL-1b within the rat hypothalamus (314, 340). The minimum doses of LPS required to measure significant increases in hypothalamic IL-1b have been reported to be between 0.15 and 1 mg/kg (intraperitoneal), and elevations have been detected as early as 1 h after LPS, with a peak increase apparent at 4 – 10 h (314, 340). Similarly bioactive IL-1 has been detected in the brains of rats (655) and mice (264) after LPS treatment, and again the doses used were large and the time required before a significant increase was measurable was long (5 – 6 h). The topographical, temporal, and cellular induction of TNF-a mRNA by LPS treatment in mice appears to be similar, but not identical, to that described for IL-1b (102). At early time points (1.5 h), hybridization signal is most prevalent over perivascular and neuronal elements in the CVO (OVLT, AP, and ME) and in the meninges. Increased hybridization signal within the brain parenchyma is not obvious 6 h after LPS, with marked induction of TNF-a mRNA in the hypothalamus and NTS being apparent only at 9–18 h after LPS (102). Increased immunoreactive TNFa concentrations in rat CSF have been detected as early as 0.5 h after a huge dose of LPS (30 mg/kg iv) (483), and significant increases in the concentrations of bioactive TNF-a and IL-6 in push-pull perfusates from the anterior hypothalamus have also been demonstrated within 1–3 h of LPS (20–50 mg/kg ip) injection in rats or guinea pigs (365, 418, 419, 705). Similar to IL-1 and TNF-a, IL-6 mRNA is induced in CVO (particularly the SFO, OVLT, ME, and AP) and the choroid plexus 3–6 h after LPS (intraperitoneal) (900). The effect of discrete localized inflammation within the periphery on cytokine expression in the brain has been less well studied. We have found no increase in either IL-1b or TNF-a mRNA using in situ hybridization or IL-1b, IL-6, or TNF-a mRNA by competitive RT-PCR at 5–8 h after intramuscular turpentine (881). Furthermore, we have been unable to detect any increase in brain homogenate content of either IL-6 or TNF-a during turpen- 23 24 ANDREW V. TURNBULL AND CATHERINE L. RIVIER / 9j0c$$oc11 P13-8 to IL-1b, but not IL-6. However, this contrasts with the findings of PVN lesioning studies that indicate an obligatory role of the PVN in the elaboration of the plasma ACTH response to a single injection of IL-6 (434). The relationship between changes in mRNA levels of neuropeptides and cIEG in the PVN and hypothalamic release of peptides and subsequent pituitary ACTH secretion thus remains unclear. Whereas ACTH secretion is observed within 5–10 min of peripheral administration of IL-1, the earliest time point reported for induction of c-fos mRNA in the PVN after peripheral IL-1b has been 30 min (187), and the earliest time reported for CRF mRNA is 1 h (98). Furthermore, the minimum dose of IL-1b required to induce Fos expression in CRF-containing neurons in the PVN is an order of magnitude greater than the minimum dose required to elicit ACTH secretion (237). Finally, marked increases in plasma ACTH concentrations (from õ20 pg/ml basal to ú700 pg/ ml) can be elicited by doses of peripheral IL-1b that do not produce measurable changes in either CRF or AVP mRNA in the pPVN (457). This disparity in minimum doses could be due to differences in the sensitivity of the detection of elevations in plasma ACTH versus the detection of induction of Fos or CRF mRNA. Alternatively, it may indicate that ACTH secretion can occur at doses of IL-1b that do not elicit changes in gene expression in the PVN. Indeed, the transcriptional/translational changes that have been observed within the pPVN may well occur as a consequence of, rather than as a cause of, increased secretory activity of PVN neurons. Consequently, the absence of detectable changes in cIEG or neuropeptide mRNA expression in the pPVN does not necessarily indicate a lack of PVN contribution to observed increases in HPA axis secretory activity. Strong evidence that IL-1 stimulates the secretory activity of the HPA axis primarily by an action on the CNS comes from studies that have demonstrated that IL-1 rapidly stimulates the secretion of CRF from the ME into hypophysial portal blood vessels. Corticotropin-releasing factor is depleted from the ME of colchicine-treated rats within 1 h of intraperitoneal IL-1b (55), and CRF concentrations in portal blood are elevated within 30 min of intravenous IL-1b (730). In the perfusates from push-pull cannulas placed within the ME, CRF concentrations are elevated within 5 min of either intracerebroventricular or intra-PVN IL-1b (40) and precede the rise in plasma ACTH after intravenous IL-1b (936, 940). Similarly, intravenous TNF-a produces an immediate rise in CRF secretion (938). Histological examination of hypophysiotropic nerve terminals suggests that AVP may (958) or may not (54) be cosecreted with CRF in response to peripheral IL-1, whereas electrophysiological data indicate that increased activity in the PVN is selective for neurons containing CRF only (728). However, in one study, the mean portal blood concentrations of AVP were almost twofold elevated by 30 min after intravenous IL-1b, although this increase did not achieve statistical significance (730). Fur- 11-25-98 11:16:36 pra APS-Phys Rev Downloaded from on April 23, 2014 is due to an action at or above the level of the hypothalamus. Indeed, surgical lesioning studies indicate the importance of an intact hypothalamus (619) to the elaboration of a plasma ACTH responses to IL-1b in the rat. Electrolytic obliteration of the rat PVN also markedly reduces the rise in plasma ACTH concentrations produced by a number of cytokines, with inhibition being complete in the cases of intracerebroventricular IL-1b (681) or intravenous IL-6 (434), Ç70% after intravenous TNF-a (434), and Ç50% when IL-1b is injected intravenously (434). Studies assessing the expression of cIEG and neuropeptide mRNA within the rat pPVN after administration of IL-1b have also suggested a CNS site of action of IL-1 administered via either peripheral or central routes. Interleukin-1b administered intravenously (237, 588, 914) or intraperitoneally (98, 128, 187, 831) induces c-fos mRNA or Fos protein expression in the rat pPVN. The Fos signal in the pPVN colocalizes with CRF immunoreactivity or mRNA after either peripheral route of IL-1b treatment (128, 237, 914), indicating cellular activation of CRF-containing neurons. Peripheral administration of large doses of IL-1b also increases CRF mRNA in the PVN (98, 237, 327). Similarly, increases in c-fos mRNA or Fos protein are elicited in the pPVN in response to intracerebroventricular IL-1b (153, 187, 588, 682, 684) and are accompanied by increased expression of not only CRF (457, 682) but also AVP mRNA in the pPVN (457). In addition to IL-1b, IL-1a also stimulates Fos expression in the pPVN after its intracerebroventricular administration (153, 381). Interleukin-1a administered intraperitoneally has been reported not to influence the expression of pPVN CRF mRNA (327). However, the fact that the doses of IL-1a used in this latter study were not sufficient to produce significant increases in plasma ACTH concentrations casts doubt on the significance of these negative findings (327). In contrast to the impact of a single injection of IL-1b on pPVN cIEG expression, a single injection of IL-6 intravenously (899), intracerebroventricularly (899), or intraperitoneally (128) has no impact on PVN cIEG expression. It should be noted, however, that the half-life of IL-6 (like other cytokines) in circulation after intravenous injection is very short. Indeed, Castell et al. (146) described a biphasic disappearance of human IL-6 from rat plasma, with an initial half-life of just 3 min. However, during inflammation, plasma IL-6 concentrations are elevated for hours or days. Therefore, the findings that constant infusion of IL-6 (589) does induce Fos expression in the pPVN (in a cyclooxygenase-dependent fashion) are clearly of relevance and indicate that circulating IL-6 can influence pPVN activity. The different effects of a single injection of IL-1b or IL-6 on pPVN neuronal activity, as assessed by Fos and CRF mRNA expression, would seem to indicate that activation of the pPVN may be a factor responsible for elevated HPA axis secretory activity produced by acute exposure Volume 79 January 1999 TABLE Cytokine IL-1a IL-1b IL-2 IL-6 IL-8 TNF-a IFN-a EGF Activin 25 REGULATION OF HPA AXIS BY CYTOKINES 7. Cytokines increase CRF secretion from the hypothalamus in vitro Preparation Static explant Superperfused hypothalami Static explant Superperfused hypothalami Dispersed cell cultures Static explant Hypothalamic slices Superperfused hypothalami Static explant Static explant Static explant Static explant Hypothalamic slices Static explant Dispersed cell cultures Minimum Doses of Cytokine Incubation Time or Time to Effect Reference No. 0.1–10 pM 100 pM 0.001–280 pM 0.6–100 pM 1 pM–10 nM 0.01–0.1 pM 20–30 min 6 min 20–45 min 5–10 min 4–20 h 30 min 20–40 min 5 min 20–40 min 30 min 20–40 min 20 min 20 min 20 min 24 h 56, 491, 854, 873 600 59, 121, 172, 315, 491, 501, 583, 653, 813, 854, 873, 999 130, 131, 133–135, 599, 600, 724 116, 346 392–394 659, 660 131 491, 500, 501, 545, 583, 813, 854 491, 854 58, 813 289 660 492 650 0.1–800 pM 30 pM 100 pM–6 nM 50 nM 1 pM 1 nM Definitions are as in Table 3. The majority of studies have quoted cytokine concentrations in terms of molarity. Only a few studies quote their concentrations in the more appropriate biological or international standard units, but these have not been included here, because without their widespread usage, they do not afford easy comparison between different studies. / 9j0c$$oc11 P13-8 of their individual effects (131). Such synergistic effects mirror the cytokine interactions that take place within the immune system (see sect. IC) and underscore the importance of applying to experimental paradigms the in vivo reality of multiple cytokine production. Although the above discussion clearly indicates that a number of cytokines influence hypothalamic neurosecretory activity, probably the best evidence that the CNS is the primary target of cytokine action on the HPA axis in vivo is derived from experiments where CRF (or AVP) has been immunoneutralized. Immunoneutralization of CRF in the rat inhibits the rise in plasma ACTH or corticosterone concentrations produced by intravenous IL-1a or -1b, IL-6, and TNF-a (55, 58, 457, 575, 730, 894, 909). The reduction in intravenous IL-1b-induced ACTH secretion produced by anti-CRF antisera/antibodies has been found to range from an 84% reduction to a complete blockade (55, 457, 730, 894). Interleukin-1b administered either intraperitoneally or intracerebroventricularly elicits ACTH secretion that can be inhibited by 85 and 73%, respectively (457). When a complete blockade of intravenous IL-1binduced ACTH secretion has been achieved, the rise in plasma corticosterone concentrations has also been totally abolished (730). However, some authors have reported only marginal effects of CRF antibodies on the plasma corticosterone response to IL-1b (intravenous) (909), but the absence of measurement of plasma ACTH levels in this study precludes determination of whether these findings can be interpreted as indicating direct actions of IL-1 on the pituitary and/or adrenal glands. Corticotropin-releasing factor antisera/antibodies/receptor antagonists also inhibit the rise in plasma ACTH concentrations produced by a number of other cytokines. Consistent with the effects of PVN lesioning, anti-CRF pretreatment totally abolishes elevations in both plasma 11-25-98 11:16:36 pra APS-Phys Rev Downloaded from on April 23, 2014 thermore, either intravenous, intra-PVN, or intra-ME IL1b causes prompt increases in both CRF and AVP concentrations in ME push-pull perfusates (939). In contrast, the intravenous injection of IL-1b does not influence hypophysial portal blood oxytocin concentrations (730). Despite the fact that no IL-1 receptors have been demonstrated in the PVN, a number of studies demonstrate that IL-1 stimulates the secretion of CRF from the hypothalamus in vitro (see Table 7). Incubation with subnanomolar doses of IL-1a or IL-1b has consistently been reported to rapidly (within minutes) increase the release of CRF from rat hypothalamic explants, superfused hypothalamic tissue, as well as dispersed hypothalamic cell cultures (see Table 7). In addition, IL-1b increases the CRF content of hypothalamic explants, indicating an increase in CRF peptide production (315). Most (121, 491, 545, 991, 992, 999), although not all, investigators (813) have noted concomitant increases in AVP secretion. However, it should be noted that AVP release from the hypothalamus may be destined, in vivo, for secretion from the posterior pituitary, rather than direct interaction with corticotropes. Similarly, IL-2, IL-6, IL-8, TNF-a, IFN-g, and EGF potently induce rapid increases in CRF (see Table 7) and/or AVP secretion (339, 658, 741) from rat hypothalami in vitro. A few studies have also demonstrated synergistic effects of various cytokine combinations on hypothalamic neuropeptide secretion. Buckingham et al. (121) demonstrated that the release of CRF and AVP by conditioned media from LPS-stimulated rat peritoneal macrophages (which contains multiple cytokines) is far greater than that observed with either IL-1a, IL-1b, IL-6, IL-8, or TNF-a alone. Indeed, a subthreshold dose of TNF-a markedly potentiates the IL-1b-induced release of AVP from hypothalamic explants (121), while the increase in CRF secretion due to IL-1b plus IL-2 is greater than the addition 26 ANDREW V. TURNBULL AND CATHERINE L. RIVIER B. Evidence for Direct Effects of Cytokines on Pituitary Adrenocorticotropic Hormone Secretion 1. Cytokine receptors within the pituitary A number of cytokine receptors have been localized in the pituitary (see Table 8). For example, 125I-labeled human IL-1a (29, 30, 177, 843, 846, 847), IL-1b (30) or ILra (841), or rat IL-1b (516) bind specifically to the anterior lobe of the mouse pituitary gland, with little or no IL-1 binding apparent in the mouse posterior pituitary (29, 30, 516). Pituitary IL-1 binding in the mouse is decreased by systemic treatment with LPS (840, 843) and increased by immobilization stress (29), ether-laparotomy stress (846, 847), and long-term treatment (7 day) with GC (29). Inter- / 9j0c$$oc11 P13-8 estingly, the increase in IL-1 binding observed in the pituitary after ether-laporotomy stress can be prevented by treating mice with a CRF receptor antagonist (847), suggesting that activation of the HPA axis secretion per se may upregulate pituitary IL-1 receptors. Although there have been many studies investigating IL-1 binding in mouse pituitary, there is only one report demonstrating IL-1 binding in the rat (516). In contrast to the mouse, both anterior and posterior lobes of the rat pituitary bind 125 I-labeled rat IL-1b (516). In addition to studies demonstrating IL-1 binding by the anterior pituitary, RT-PCR experiments have demonstrated the presence of both IL-1R1 and IL-1R2 mRNA in the whole mouse pituitary (626). In situ hybridization histochemistry experiments agree with IL-1 binding studies and show that IL-1R1 mRNA is present in the mouse anterior, but not posterior, pituitary (178). Interleukin-1 binding and IL-1R1 and IL-1R2 mRNA have also been demonstrated in the mouse corticotropic tumor cell line AtT20 (110, 111, 423, 872, 947). Interestingly, and in accordance with the stress-induced increases in IL-1 binding in the anterior pituitary of the mouse (847), CRF increases IL-1a binding in AtT20 cells (947), while IL-1b and TNF-a increases the expression of both IL-1R1 and IL-1R2 mRNA (110). However, the expression of IL-1R1 and IL-1R2 by AtT20 cells does not necessarily indicate that normal corticotropes contain cell-surface IL-1 receptors. Indeed, when IL-1R1 and IL-1R2 immunoreactivities were localized to particular endocrine cell types in the normal mouse anterior pituitary, no evidence of colocalization of IL-1 receptor with ACTH was apparent (267). Immunolabeling using a panel of IL-1 receptor antibodies demonstrated that IL-1R1 and IL-1R2 were abundantly expressed in the mouse anterior pituitary, were always coexpressed, and were predominantly localized to a single cell type, the somatotrope (growth hormone-producing cells) (267). However, the possibility that IL-1 receptor expression by corticotropes is below the limits of the immunohistochemical techniques employed, or that the level of IL-1 receptor expression may be induced (as demonstrated in AtT20 cells), cannot be excluded. Much less work has focused on the presence of IL-6 and TNF-a receptors within the pituitary. Rodent anterior pituitaries exhibit binding of 125I-labeled IL-6 (601), and IL-6Ra mRNA is expressed in normal rat (601, 915) and fetal and adult human pituitaries (774, 915). Interleukin-6Ra is also expressed in human ACTH and growth-hormone secreting tumors (675, 915). In addition, the IL-6R signaling subunit gp130 is present in human fetal pituitary cells (774). High concentrations of binding sites for rmTNF-a have also been demonstrated in the mouse and rat anterior pituitaries (967), AtT20 cells (422), and the folliculostelate cell line TtT/GF (422). 11-25-98 11:16:36 pra APS-Phys Rev Downloaded from on April 23, 2014 ACTH and corticosterone concentrations produced by IL6 (575, 909), whereas inhibition of intravenous TNF-ainduced ACTH secretion by anti-CRF is nearly complete (58), with only a small corticosterone response remaining (58, 909). Administration of the CRF receptor antagonist a-helical CRF-(9{41) inhibits the rise in plasma ACTH due to EGF (551), but not NGF (741). However, the low potency of this receptor antagonist at the pituitary CRF receptor (888, 891) makes interpretation of incomplete inhibition of ACTH secretion difficult. The effect of immunoneutralization of AVP on cytokine-induced ACTH secretion has been less well studied. We have consistently observed a 15–20% decrease in the plasma ACTH response to peripherally administered IL1b when rats are pretreated with anti-AVP, although these effects are not always statistically significant (457, 687; unpublished observations). However, we also find that immunoneutralization of AVP inhibits the ACTH response to CRF itself by Ç20–30% (892). Thus the role of AVP in peripheral IL-1b-induced ACTH secretion is probably only permissive and is required only to permit the full expression of the ACTH secretagogue capacity of CRF. However, when IL-1b is administered intracerebroventricularly, the effects of AVP neutralization are more pronounced (40% inhibition), a finding consistent with the stimulatory effects of intracerebroventricular IL-1b on pPVN AVP mRNA and which suggests an activational role of AVP in the ACTH response to intracerebroventricular IL-1b (457). Collectively, the rapid effects of IL-1 and other cytokines on hypothalamic CRF secretion in vivo and in vitro, together with the reduction of plasma ACTH responses to cytokines produced by inhibiting the actions of CRF, provide an extremely strong case for the CNS as a primary site of cytokine action in the stimulation of HPA axis secretory activity. Nevertheless, a large number of in vitro studies have also indicated the possibility of direct effects of cytokines on pituitary ACTH secretion and adrenal GC secretion. Volume 79 January 1999 TABLE 27 REGULATION OF HPA AXIS BY CYTOKINES 8. Cytokine receptors in pituitary Cytokine Receptor IL-1 IL-2 IL-6 TNF-a LIF OM Activin EGF FGF PDGF (a and b) Neurotrophin receptors Reference No. AtT20 cells Normal mouse anterior pituitary Normal rat anterior and posterior pituitary AtT20 cells Human corticotropic adenoma Rat anterior lobe, ACTH-containing cells Normal rat anterior rat pituitary Human fetal pituitary (IL-6Ra and gp130) Normal human pituitary Human pituitary tumors Normal rat and mouse anterior lobe AtT20 cells Folliculostellate cells Human pituitary fetal cells, ACTH cells AtT20 cells Human pituitary fetal cells AtT20 cells Normal rat pituitary GH3 rat pituitary tumor cells Rat anterior lobe Sheep anterior lobe Normal anterior and posterior lobes Human pituitary adenomas Normal human anterior lobe Rat anterior lobe Rat anterior pituitary, lactotropes GH3 rat pituitary tumor cells Rat anterior pituitary Rat anterior and posterior Rat anterior and intermediate 29, 30, 110, 111, 178, 267, 423, 516, 517, 626, 840, 843, 846, 847, 872, 947 22, 796 601, 675, 774, 775, 915 422, 967 7, 774 774 136, 155, 521 151, 244, 562 298 464 244 155, 188 431, 631 Definitions are as in Table 3. 2. Cytokine expression in the pituitary The pituitary has been shown to produce a diverse range of cytokines (see Table 9 and an excellent review by Ray and Melmed, Ref. 666). Some of these cytokines (e.g., IL-2, IL-10, LIF, and MIF) have been localized to corticotropes or demonstrated in the corticotrope cell line AtT20 (7, 22, 61, 119, 350). In vivo mRNA encoding the cytokines IL-1a, IL-1b, IL-6, LIF, IFN-g, and TNF-a mRNA in the pituitary are all elevated by 45 min to 6 h after treatment with LPS (277, 424, 453, 570, 644, 748, 865, 926). Anterior pituitary IL-6 mRNA is also increased by chronic, local inflammation (732, 818). The constitutive expression of IL-1ra in the pituitary (269, 277, 471, 971) is of particular interest given its ability to antagonize the effects of IL-1 agonists, suggesting that the responsiveness of the pituitary to IL-1 may be modulated at a local level. Interleukin-1ra mRNA has been reported to be either unaffected (277) or induced (269, 471, 971) by systemic treatment with LPS. One cytokine in particular, MIF, has been proposed to serve as a pituitary hormone (60, 118–120, 126). Bucala and co-workers (60) isolated a 12.5-kDa protein from the conditioned media of LPS-stimulated mouse pituitary cells, which was subsequently sequenced, its cDNA cloned, and identified as the mouse homolog of human / 9j0c$$oc11 P13-8 MIF (60, 61, 118, 119). The mouse pituitary contains large amounts of preformed, intracellular pools of MIF (possibly located within corticotropes) which are released into the systemic circulation after treatment with LPS. Macrophage migrating inhibitory factor appears in the blood of normal mice within 2 h of LPS treatment, and its serum concentration continues to rise for Ç20 h. No MIF is detectable in the serum of hypophysectomized mice 20 h after LPS, suggesting a pituitary origin of MIF found in serum. Macrophage migrating inhibitory factor appears to play a critical role in host defense to endotoxemia, since LPS-induced lethality in mice is potentiated by coadministration of MIF, whereas an anti-MIF antibody confers protection from lethal doses of LPS (60). Corticotropin-releasing factor increases the secretion of MIF from AtT20 cells, at doses lower than those required to stimulate ACTH secretion, suggesting that MIF secretion may increase in parallel with activation of the HPA axis (591). Although itself proposed as a pituitary hormone, the effects of MIF on the secretion of other pituitary hormones (e.g., ACTH) have not been characterized. The regulation of IL-6 secretion from anterior pituitary cell cultures has been investigated extensively. Anterior pituitary cells constitutively produce IL-6 (807), and the secretion of this cytokine can be induced within 6 h of treatment with LPS (801, 806, 886), IL-1a, IL-1b (801, 11-25-98 11:16:36 pra APS-Phys Rev Downloaded from on April 23, 2014 TGF-a TGF-b Localization 28 ANDREW V. TURNBULL AND CATHERINE L. RIVIER TABLE 9. Cytokines in the pituitary Cytokine IL-1a IL-1b IL-1ra IL-2 IL-6 IL-8/cinc/gro IL-10 TNF-a LIF IFN-g Activin BDNF EGF bFGF NGF PDGF (A and B subunits) TGF-a TGF-b Whole rat pituitary Rat anterior pituitary Whole rat or mouse pituitary Human pituitary adenomas Whole rat pituitary AtT-20 Human corticotropic adenoma Rat, mouse, pig, or sheep anterior or whole pituitaries Normal rat anterior pituitary cell cultures Human pituitary tumors Folliculostellate cells Rat neurointermediate lobe Rat anterior pituitary AtT-20 Mouse pituitary Human pituitary Whole mouse or rat pituitary Human fetal pituitaries Normal mouse pituitary Bovine pituitary folliculostellate cells Normal sheep pituitary Mouse anterior pituitary Corticotrophs and thyrotrophs Rat whole pituitary Gonadotropes Rat anterior and intermediate lobes Rat anterior pituitary Rat folliculostellate cells Rat anterior pituitary Whole human pituitary Rat anterior pituitary Human pituitary adenomas Normal human anterior pituitary Rat anterior pituitary Bovine anterior pituitary Rat anterior pituitary Reference No. 277 277, 424, 453, 644 471, 734, 971 22 1, 11, 277, 453, 570, 644, 818 145, 508, 579, 802– 806, 853, 986 375–378, 675, 874, 895 801, 912, 913 426 350, 662 277, 453, 644, 756 7, 258, 756, 774, 926 60, 118, 119 644 75 431, 797 244, 245, 562 13 298 518 164, 549, 631, 632 464 244 564 731 Definitions are as in Table 3. 805, 806), TNF-a (579), the IFN family (986), phorbol myrisate, and agents that elevate cAMP (803, 807). Accordingly, dibutyryl cAMP, prostaglandin E2, forskolin, and cholera toxin all increase IL-6 secretion from rat anterior pituitary cell cultures (145, 802, 805, 806). Some [vasoactive intestinal peptide (VIP), pituitary adenylate cyclase activating peptide (PACAP), and calcitonin gene-related peptide] but not all (CRF, growth hormone releasing factor) neuropeptides that utilize cAMP-coupled receptors for signaling, therefore, also stimulate IL-6 secretion in anterior pituitary cells (803, 853, 886). However, the induction of IL-6 secretion from anterior pituitary cells by IL1b does not appear to be mediated by cAMP-dependent pathways, since in these cells, no increase in intracellular cAMP is apparent after treatment with IL-1b (802, 804– 806, 808). Glucocorticoids inhibit basal (145) and IL-1bstimulated (806) IL-6 release from rat anterior pituitaries. / 9j0c$$oc11 P13-8 In addition to secretion from anterior pituitary cells, IL-6 is released by neurointermediate lobe cells in culture, with IL-1b and LPS again being potent secretagogues (801). The cell source within the normal anterior pituitary does not appear to be a classical endocrine cell type. Rather, folliculostellate (FS) cells are the major sources of IL-6 (11, 912, 913). Folliculostellate cells are of monocytic lineage and are thought to be involved in paracrine regulation of hormone secretion from the pituitary (26). Recently, an FS-like cell line has been isolated (TtT/GF), and in accordance with previous studies on whole anterior pituitaries, TtT/GF cells constitutively secrete IL-6, and IL-6 secretion is enhanced by TNF-a, VIP, PACAP (422, 522) or IL-1b (L. Bilezikjian and A. V. Turnbull, unpublished observations). 3. Direct effects of cytokines on pituitary ACTH secretion in vitro With the exception of activin, which inhibits POMC mRNA expression and ACTH secretion in the corticotropic tumor cell line AtT20 (74), and reduces ACTH secretion from primary cultures of rat anterior pituitary cells (75), all other cytokines studied have been reported to either enhance or have no effect on either ACTH secretion or POMC mRNA expression in otherwise untreated pituitary cells (see Table 10). The effects of cytokines on the mouse anterior pituitary tumor cell line AtT20 are reasonably undisputed. Similarly, IL-1b, IFN-g, and GMCSF stimulate ACTH secretion from cultured human pituitary adenoma cells from patients with Cushing’s disease (512). The duration of exposure of AtT20 cells and human pituitary adenoma cells to cytokines required to elicit statistically significant increases in ACTH secretion has, in general, been long. Although one report indicates increases in ACTH produced by either IL-1 or IL-6 within 2 h (966), the majority have used incubation times ranging from 6 to 72 h (7, 115, 243, 268, 667, 816). The fact that many cytokines have a stimulatory effect on pituitary tumor cells indicates the ability of signal transduction pathways activated by cytokine-cytokine receptor interaction to influence POMC expression and/or ACTH secretion. However, it is unclear to what extent corticotrope tumors accurately represent normal anterior pituitary corticotropes. For example, although AtT20 cells possess both IL-1R1 and IL-1R2 mRNA (110, 198, 872, 947), immunostaining of normal mouse pituitary does not show significant IL-1 receptor expression by corticotropes (267). Most important to the present discussion, however, is that although most cytokines tested increase ACTH secretion from AtT20 cells, their effects on normal rat anterior pituitaries have been extensively debated (see Table 10). Although the effects of a number of cytokines on in vitro anterior pituitary preparations have been investigated (see Table 10), by far the best studied has been the 11-25-98 11:16:36 pra APS-Phys Rev Downloaded from on April 23, 2014 MIF Localization Volume 79 January 1999 REGULATION OF HPA AXIS BY CYTOKINES 10. Direct effects of cytokines on ACTH secretion from the pituitary TABLE AtT-20 Cytokine Effect IL-1a 115, 268 IL-1b 115, 243, 268, 312, 717 IL-2 IL-6 115, 796 268, 966 IL-8d IL-10 LIF OM TNF-a No effect 268 350 7, 95, 667, 816 7, 667, 816 422 Effect No effect 402 825a 48, 62, 115, 116, 132, 329, 402, 893 825a 893b 115, 395 499, 774 527c 737c 491, 629, 730, 873, 893 25, 55, 96, 366, 491, 583, 628, 629, 873 583 491, 498, 583 491 774 774 540 58b 74 897 156 NGF 402, 583 275e 491e 492, 551 289, 583 583 913g 741 Reference numbers for corresponding studies are given. Unless otherwise stated, effect of cytokines is to increase either ACTH secretion a or proopiomelanocortin (POMC) mRNA expression. Neither IL-1a nor IL-1b affected ACTH secretion or POMC mRNA expression after 3 h incubation, but either IL-1a or IL-1b increased ACTH secretion after 3 h, with only IL-1b producing a statistically significant increase in POMC b mRNA. Significant increases observed only at doses of 100 nM and c d greater. Stimulation described as ‘‘weak’’ or ‘‘slight.’’ References with regard to IL-8 include the homologous cytokines cinc/gro/ e NAP-1. TNF-a had no effect on basal ACTH secretion but inhibited f CRF- or hypothalamic extract-induced ACTH secretion. Unlike all other cytokines listed, activin decreases POMC mRNA expression and g IFN-g ACTH secretion in AtT20 cells and rat anterior pituitary cells. did not affect basal but inhibited CRF-stimulated ACTH secretion. Definitions are as in Table 3. influence of IL-1. However, this literature is confusing. Indeed, of the three original articles demonstrating the potent effects of IL-1 on ACTH secretion in the rat, one described a direct effect on pituitary cells in culture (62), whereas the other two found no effect (55, 730). Subsequent studies have not clarified this apparent discrepancy (see Table 10). Although some have shown stimulatory effects of IL-1b but not IL-1a (893), others have reported that either will enhance ACTH secretion directly from the anterior pituitary in vitro (402, 825). A greater proportion of positive findings have been obtained when using pituitary tissue obtained from female rats (62, 402, 873, 893). However, when directly compared, the male and female pituitary responded to IL-1b in an identical manner (893), and there have been reports of a stimulatory influence of IL-1 in male pituitaries (116, 132, 329) and no effect in females (55). The use of different anterior pituitary prepa- / 9j0c$$oc11 P13-8 rations does not seem a likely explanation for the contradictory data obtained, since either positive or negative results have been obtained using either static dispersed rat anterior pituitary cell cultures (55, 62, 402, 730), perifused dispersed rat anterior pituitary cells (132, 583, 873), or perifused rat anterior pituitary segments (48, 116, 329, 628, 629). Furthermore, whether IL-1 potentiates the ACTH response to CRF has also been disputed (55, 96, 132, 366, 629, 635, 873, 893). It should be noted that virtually all studies employed pituitary preparations that are capable of enhanced ACTH secretion, as shown by a stimulatory effect of CRF. Of particular interest to the issue of whether cytokines directly stimulate ACTH secretion in vitro is the influence of time of incubation. The studies that have used long incubation periods (7 h or more) have all reported a significant effect of IL-1b on ACTH secretion. Indeed, IL1b has been found to enhance ACTH secretion at 8–24 h but not at 4 h (402), at 15 h but not 3 h (825), and at 7– 30 h but not at 3 h (329). However, given the rapid effects of IL-1 on ACTH secretion in vivo (within 5–10 min), the majority of in vitro studies have focused on shorter incubation times. Some studies have demonstrated increased ACTH secretion within minutes of IL-1b application to perifused anterior pituitary cells (48, 132), within 1 h of incubation in rat anterior pituitary cell cultures (116), whereas others indicate effects on ACTH secretion by rat anterior pituitary cell cultures at picomolar to nanomolar doses at 4 h (62), or only at high doses (100 nM) at 2 h (893). The majority, however, report no effect of IL-1 within 3 h of incubation of rat anterior pituitary preparations with either IL-1a or IL-1b (25, 55, 96, 329, 366, 402, 491, 583, 628, 629, 730, 825, 873). As with IL-1, studies of the direct ACTH stimulating effects of IL-2, IL-6, IL-8, TNF-a, and EGF in vitro have been contradictory (see Table 10). Although it may be contentious to equate the different in vitro preparations, it is interesting to note that where hypothalamic explants and pituitary cell cultures have been compared within the same study, hypothalamic CRF and/or AVP release is induced more rapidly and at much lower concentrations of IL-1b (873), IL-6 (583), TNF-a (58), IFN-g (289), NGF (741), and EGF (492) than those required to elicit pituitary ACTH secretion. However, it should be noted that, despite the well-known synergistic effects of cytokines within the immune system, there is little known about possible synergistic effects of cytokines on pituitary ACTH secretion in vitro. This may be of particular relevance given that Buckingham et al. (121) demonstrated that although neither IL-1a, IL-1b, IL-6, IL-8, nor TNF-a alone affects ACTH secretion from rat anterior pituitary fragments (491), conditioned media from macrophages stimulated with LPS produce a dose-dependent increase in ACTH secretion within just 30 min (121). 11-25-98 11:16:36 pra APS-Phys Rev Downloaded from on April 23, 2014 Activinf EGF IFN-a IFN-g Anterior Pituitary Cells 29 30 ANDREW V. TURNBULL AND CATHERINE L. RIVIER C. Evidence for Direct Actions of Cytokines on Adrenal Glucocorticoid Secretion 1. Cytokine receptors within the adrenal To our knowledge, there are only very few published studies of the presence of cytokine receptors within the adrenal gland. The adrenal gland displays no positive in situ hybridization signal for IL-1R1 mRNA (178), whereas IL-6Ra mRNA has been detected mainly in the zona glomerulosa and fasciculata in human adrenals (630) and also in the adrenal medulla (272). 2. Cytokine expression in the adrenal gland / 9j0c$$oc11 P13-8 produce IL-6, dexamethasone does not influence either basal or IL-1b-stimulated IL-6 secretion in zona glomerulosa cells (383). Intriguingly, ACTH increases the release of IL-6 from zona glomerulosa cells but not zona fasciculata/reticularis, despite similar ACTH-stimulated cAMP levels in each cell type (383). Such ACTH-induced IL-6 release from the adrenal suggests that activation of the HPA axis per se may cause IL-6 secretion from the adrenal (383). Like IL-6, TNF-a secretion is stimulated by protein kinase C activators and ionomycin (384). However, in stark contrast to IL-6, basal and stimulated TNF-a release is dose dependently inhibited by ACTH and dibutyryl cAMP (384). Similarly, differential effects on IL-6 and TNF-a secretion from zona glomerulosa cells are observed with serotonin and adenosine (676, 677). 3. Direct effects of cytokines on adrenal glucocorticoid secretion Despite a lack of evidence for the presence of IL-1, IL-6, or TNF-a receptors within the adrenal gland, direct actions of these cytokines on GC secretion have been demonstrated. In vivo, peripheral administration of IL-1b has been reported to either stimulate (14) or exert no effect (310) on corticosterone secretion in hypophysectomized rats and to induce secretion of GC in anesthetized rats with isolated adrenal glands (698). The doses required to observe direct effects of IL-1b on adrenal corticosterone secretion in vivo have, however, been extremely high (35 mg/rat, Ref. 698), which casts doubt on the physiological relevance of this effect. In vitro studies have indicated that IL-1b does not influence either basal or ACTH-stimulated GC production from human fetal adrenal tissue either in cell or organ culture (328). However, either IL-1a or -1b increases GC secretion from rat quartered adrenals (311), rat adrenal slices (14), and rat, bovine, and human dispersed adrenal cells (311, 528, 597, 867, 957, 964). Similarly, IL-2, IL-3, and IL-6 induce GC secretion from various adrenal cell preparations (180, 630, 867, 946), and IL-6 potentiates corticosterone secretion induced by low concentrations of ACTH (722). Tumor necrosis factor-a stimulates cortisol secretion from adult adrenocortical cells (180) but inhibits ACTH-induced cortisol secretion from human fetal adrenal tissue (361) and cultured cells (362). Interferon-g stimulates corticosterone secretion from primary dispersed rat adrenal cells (289) and normal human adrenal slices (143), whereas NGF does not influence either basal or ACTH-stimulated corticosterone production from dispersed rat adrenal cell cultures (741). These in vitro studies provide strong evidence that some cytokines may influence GC secretion directly. However, it should be noted that of the studies cited, 11-25-98 11:16:36 pra APS-Phys Rev Downloaded from on April 23, 2014 In the adrenal gland, large constitutive pools of IL1a and IL-1b have been identified (42, 753, 754). Interleukin-1a, IL-1b, and IL-1ra immunoreactivties have been demonstrated in adrenal chromaffin cells (42, 753, 754). In addition, IL-1a, IL-1b, ICE, and IL-1ra mRNA are present in the adrenal cortex and are markedly elevated in both adrenal medulla and cortex 90 min after intravenous or intraperitoneal LPS (594, 754, 866). Interestingly, the IL-1-related cytokine IL-18/IL-1g is also synthesized within the rat adrenal cortex, mainly in the zona reticularis and fasciculata, and is strongly induced by acute cold stress (166). Interleukin-6 mRNA is also present throughout the human adrenal cortex (299, 630), and rat adrenal gland extracts contain IL-6 mRNA (272, 570, 748), which is markedly induced 2 h after intraperitoneal LPS (570). Although TNF-a mRNA has been described throughout the cortex of human adult adrenals, particularly in steroid-producing cells (300), TNF-a immunoreactive protein has been detected in only 12 of 22 fetal, and in 0 of 7 adult, human adrenals (361). A number of growth factors are also present in the adrenal: basic fibroblast growth factor mRNA or protein is present in whole human adrenals or in rat or bovine cortex or medulla (44, 301, 306, 341, 537, 757, 955), TGF-b1 mRNA and protein in bovine adrenal cortex and mouse whole adrenal (255, 341, 410, 861, 961), and NT-3 protein has been reported in whole rat adrenal (396). Studies of primary cultures of dispersed adult rat adrenal glands have indicated the likely cellular sources and major secretagogues of the cytokines IL-6 and TNFa within the adrenal gland. Although the zona fasciculata/reticularis produce small amounts of TNF-a and IL6, the primary source of IL-6 in the rat adrenal is the zona glomerulosa (382 – 385). The secretion of TNF-a and IL-6 from adrenal glomerulosa cells is stimulated in a dose-dependent manner by LPS, IL-1a, and IL-1b (383 – 385). Furthermore, IL-6 secretion from these cells is enhanced by protein kinase C activators, the calcium ionophore ionomycin, prostaglandin E2 , forskolin, and angiotensin II (382, 385). Unlike most cell types that Volume 79 January 1999 REGULATION OF HPA AXIS BY CYTOKINES the majority required incubations in excess of 12 h to observe significant effects of cytokines on GC secretion. Indeed, in a comprehensive series of studies by van der Meer et al. (906), either IL-1a, IL-1b, IL-2, IL-6, or TNFa had no significant effect on GC secretion from isolated rat adrenal cells inside 60 min, but a small stimulation was apparent Ç4 h after completion of a 6-h incubation with IL-1b. Thus, as with the effects of cytokines directly on the pituitary, it seems unlikely that a direct action of a cytokine on the adrenal can account for the rapid in vivo effects of administered cytokines on plasma GC concentrations. V. MECHANISMS OF HYPOTHALAMICPITUITARY-ADRENAL AXIS ACTIVATION BY INTERLEUKIN-1 A. Direct Actions on Pituitary and Adrenal The majority of in vivo data indicate that stimulation of pituitary ACTH and adrenal GC secretion in re- / 9j0c$$oc11 P13-8 sponse to the presence of IL-1 is produced by enhanced secretion of hypothalamic ACTH secretagogues, in particular CRF. This is evidenced by the marked reductions in plasma ACTH and corticosterone concentrations when CRF is immunoneutralized. However, incomplete inhibition of either ACTH or corticosterone secretion after CRF immunoneutralization has been observed (e.g., Ref. 909). Furthermore, marked elevations in plasma corticosterone concentrations have been noted even when ACTH secretion produced by IL-1 has been markedly reduced (e.g., Ref. 390). However, decisive evidence that CRF has been completely immunoneutralized or that the ACTH secretion remaining is unable to produce marked elevations in plasma corticosterone concentrations is often lacking. Although plasma ACTH concentrations can be elevated to levels of 1,000 pg/ml by intravenous IL-1b, much lower levels (100 – 200 pg/ ml) of ACTH are sufficient to stimulate corticosterone secretion maximally. Indeed, the adrenals of both rats and dogs have been shown to respond to very small elevations (°10 pg/ml) in plasma ACTH with significant elevations in plasma GC (388, 405, 975). The data discussed in section IV indicate that a number of cytokines, and IL-1 in particular, may be capable of having direct actions on the pituitary to enhance the secretion of ACTH and on the adrenal cortex to increase GC secretion. Receptors for IL-1 are clearly present in the anterior pituitary, although it is unlikely that these are expressed on normal corticotropes. The pituitary and adrenals clearly would be exposed to IL-1 if its concentrations in blood were elevated (e.g., severe endotoxemia). In addition, IL-1 can be synthesized locally within these tissues. However, as discussed above, it seems clear that prolonged exposure of the pituitary or adrenals to IL-1 is necessary to elicit the release of ACTH or GC, respectively. Therefore, direct actions of IL-1 on either the pituitary or adrenal do not appear to account for a significant component of the hormone secretion observed in response to acute exposure to IL-1 in vivo. In contrast, circumstances involving prolonged increases in cytokines, for example, during chronic inflammation (732, 818), may well involve direct actions of IL-1 or other cytokines on the pituitary ACTH and/or adrenal GC secretion. Furthermore, enhanced pituitary or adrenal synthesis of IL-1 may regulate these glands’ growth and development (21, 669, 819, 1004). Similarly, a number of other interleukins (e.g., IL-2, IL-6) and growth factors (e.g., EGF) have been shown to influence the growth of the pituitary or adrenal glands (20, 21, 157, 637). A large body of evidence indicates that the level of the HPA axis primarily affected by IL-1 is the hypothalamus. This is true whether IL-1 has been administered directly into the brain or into the periphery. This raises the question of how a blood-borne, large, hydrophilic peptide such as IL-1 accesses the CNS to influence hypo- 11-25-98 11:16:36 pra APS-Phys Rev Downloaded from on April 23, 2014 The above discussion details the ability of a number of cytokines from various families to significantly influence the activity of the HPA axis. Furthermore, the distributions of various cytokines and their receptors throughout the brain, pituitary, and to a lesser extent the adrenal provide an anatomic basis for the hypothesis that cytokines influence the function of these organs. However, in general, the evidence that cytokine receptors, and IL-1 receptors in particular, are expressed by secretory cells (hypophysiotropic CRF neurons, normal corticotropes, GC-producing adrenocortical cells) is not strong. This has suggested the involvement of structural and/or pharmacological intermediates in activation of the HPA axis by cytokines. Studies aimed at elucidating the mechanisms by which particular cytokines may activate the HPA axis during a particular threat to homeostasis have focused on the cytokine IL1 and to a much lesser extent IL-6 and TNF-a. The following sections discuss the proposed anatomic and pharmacological pathways by which IL-1 generated in response to a particular threat to homeostasis may influence the HPA axis and are summarized in Figure 4. The studies described in section IV indicate that the CNS is probably the primary site of IL-1 action in eliciting increased HPA axis secretory activity. Because the question of how IL-1 signals the brain is relevant to all CNS-mediated acute phase responses, such as fever, hypermetabolism, cachexia, suppression of reproduction, and sickness behavior, knowledge derived from studies of such responses is mentioned wherever pertinent. Furthermore, what information is available for other cytokines, in particular IL-6 and TNF-a, is also discussed. 31 32 ANDREW V. TURNBULL AND CATHERINE L. RIVIER Volume 79 FIG. 4 Proposed models by which interleukin-1 influences secretory activity of hypothalamic-pituitary-adrenal axis. AP, area postrema; BBB, blood-brain barrier; CVO, circumventricular organs; ME, median eminence; OVLT, organum vascularis of lateral terminalis; PVN, paraventricular nucleus; CNS, central nervous system; NTS, nucleus tractus solitarius. Downloaded from on April 23, 2014 thalamic secretions, and the models which have been proposed to address this question are discussed below. These include the possibilities that IL-1 penetrates the BBB to enter brain parenchyma (see sect. VB) or that IL-1 stimulates the production of intermediary signals (see sect. VC), by actions at the BBB interface (see sect. VD), at regions of the brain relatively devoid of a BBB (see sect. VE), at brain stem medullary cell groups (see sect. VF), and/or peripheral afferent nerves (see sect. VG). The hypothesis that IL-1 generated within the brain itself produces activation of the HPA axis is also considered (see sect. VH). Finally, the possibility that increased secretion of IL-1 locally in damaged or diseased tissue can activate the HPA axis indirectly by inducing the synthesis and secretion of a circulating factor is also discussed (see sect. VI). / 9j0c$$oc11 P13-8 B. Penetration of Cytokines Into Brain The transport of solutes out of vascular compartments and into perivascular tissue (or vice versa) occurs via either paracellular or transcellular mechanisms. Within the cerebrovaculature, the paracellular route is particularly impermeable due to the presence of the BBB. The BBB consists primarily of nonfenestrated endothelial cells that are connected by tight junctions and thus form a continuous cell layer that has the permeability properties of a continuous plasma membrane (664). The paracellular ultrafiltration of solutes into and out of tissues that occurs in peripheral vascular beds does therefore not occur in most cerebrovascular beds, at least while the BBB remains intact. Furthermore, the large molecular size (8– 65 kDa) and hydrophilic nature of cytokines preclude 11-25-98 11:16:36 pra APS-Phys Rev January 1999 REGULATION OF HPA AXIS BY CYTOKINES their movement transcellularly by simple diffusion to any appreciable extent. Indeed, early studies concluded that the BBB was impermeable to IL-1 (85, 161, 204). However, transport of cytokines via the paracellular route can occur when BBB integrity is compromised (see sect. VB1), and saturable transcellular transport mechanisms for a number of cytokines have now been described (see sect. VB2). 1. Cytokines and blood-brain barrier integrity 2. Carrier-mediated transport of cytokines across the blood-brain barrier Work by Banks et al. (34) has shown that transcellular, saturable transport mechanisms afford a means of / 9j0c$$oc11 P13-8 cytokine entry into the brain, even when BBB integrity is not compromised. These include saturable transport mechanisms for IL-1a (35), IL-1b (37), IL-1ra (309), IL-6 (36), and TNF-a (308) but not IL-2 (923). Such transport mechanisms have been described by injecting 125I-labeled cytokines intravenously in mice and measuring radioactivity in either whole brain, whole brain perfused free of blood contamination, CSF, or brain parenchymal homogenates depleted of brain capillaries. It should be noted that at the doses of cytokines used, no perturbation of BBB integrity was apparent as indicated by the low and unaltered rates of 125I-labeled albumin entry into the CNS. Not all radioactive material found in brain after intravenous cytokine chromatographically elutes as authentic cytokine. In particular, only 16% of radioactivity in brain parenchyma after intravenous 125I-labeled IL-6 was intact IL6 (36), which raises the question of how much of the 125 I-labeled IL-6 entering the brain is actually biologically active. Nevertheless, multiple time regression analyses and competition with unlabeled cytokines has demonstrated that such transport of radioactivity into brain is saturable. The members of the IL-1 family, IL-1a, IL-b, and IL-1ra share the same transporter(s) (309, 647), but IL-6 entry into brain is not inhibited by the presence of unlabeled IL-1a or TNF-a (36), whereas competition studies with IL-1a, IL-1b, IL-6, and MIP-1a have demonstrated selectivity of the TNF-a transporter (308). These studies by Banks et al. (34) have demonstrated that peak values between 0.05 and 0.3% of the total dose of either 125I-labeled IL-1a, IL-1b, IL-1ra, IL-6, or TNF-a is found in each gram of whole brain tissue by 20–60 min after their intravenous injection. Many have questioned whether this amount of cytokine entry into brain is physiologically significant (678, 711, 943). Indeed, it seems unlikely that such a small proportion of cytokine entering the brain via a saturable transport mechanism can exert rapid effects, such as those observed after intravenous injection of recombinant cytokine. Furthermore, it is improbable that transport of IL-1 across the BBB significantly accounts for the effects of peripherally administered IL-1 on the HPA axis, since the pattern of neuropeptide gene and cIEG expression and the temporal profile of ACTH secretion differs markedly between peripheral and central administration (see sects. IIA and IVA3). It nevertheless seems plausible that such transport mechanisms across the BBB may play a significant role when peripheral blood levels of endogenous cytokines are elevated for longer periods of time. This would seem particularly pertinent when considering chronic inflammation where plasma IL-6 levels can remain elevated for prolonged periods (hours to weeks). C. Role of Readily Diffusible Intermediates The apparent lack of IL-1 receptors within neuronal elements in the pPVN and the limited entry of IL-1 into 11-25-98 11:16:36 pra APS-Phys Rev Downloaded from on April 23, 2014 Loss of BBB integrity may occur during inflammatory insults to the brain such as those accompanying CNS disease (e.g., multiple sclerosis, meningitis, brain tumors, AIDS dementia), brain trauma, cerebrovascular lesions, or seizures (368). Furthermore, administration of large doses of LPS can increase BBB permeability (91, 199, 483, 496, 781, 878). Such disruption of the BBB enables not only the passage of large peptides such as cytokines, but also augments the rate of entry of cells, such as macrophages, monocytes, lymphocytes, and neutrophils, which are capable of cytokine synthesis and secretion, but whose passage into the normal, healthy brain is very limited. The association between peripheral inflammatory events and the CNS production of cytokines has led to a number of studies investigating the possible influence of cytokines on BBB permeability. In monolayer cultures of cerebral endothelial cells, either LPS or IL-1b, IL-6 or TNFa produces a decline in transendothelial electrical resistance data supportive of an elevation in BBB permeability (199, 200). In vivo studies have demonstrated that intracerebroventricular TNF-a increases BBB permeability in the rat (413) and pig (535), and enhanced brain TNF-a production has been linked to the increased BBB permeability associated with a number of CNS inflammatory conditions (768, 769, 780). However, the ability of systemic administration of cytokines (IL-1a, IL-1b, IL-2, IL-6, TNF-a) to influence BBB integrity has been debated (33, 229, 413, 719). Furthermore, experiments demonstrating increased BBB after peripheral administration of LPS have either used exceedingly high doses (483) or have observed increased BBB permeability only over a protracted time course (496). Enhanced BBB permeability as a result of either CNS or severe peripheral infection may therefore permit the entry of cytokines themselves or cytokine-producing cells into the CNS, and cytokines so derived may contribute to CNS-mediated acute phase responses. However, it is clear that the initial neuroendocrine effects of peripherally administered cytokines or LPS can be observed more quickly, and at lower doses, than can be accounted for by damage to the BBB. 33 34 ANDREW V. TURNBULL AND CATHERINE L. RIVIER the CNS have led to the hypothesis that IL-1 stimulates the HPA axis via enhancing the production of intermediates that directly interact with hypothalamic neurosecretory processes. These intermediates include classical neurotransmitters, such as catecholamines (see sect. VF), serotonin (285, 477, 478), histamine (293, 421, 638), and more readily diffusible agents such as the lipid autacoids, eicosanoids, and the gaseous mediator nitric oxide (NO) (see sect. VC2). 1. Eicosanoids / 9j0c$$oc11 P13-8 plasma ACTH concentrations from the pituitary, the direct effect of PGE2 on pituitary ACTH secretion in vitro appears to be inhibitory (921). Collectively, these data suggest that the stimulatory actions of PG on ACTH secretion in vivo are exerted at the level of the hypothalamus or elsewhere within the CNS. The majority of studies investigating the effects of IL-1 or LPS on PG formation have focused on PGE2 , which is elevated in the systemic blood of either rats or rabbits injected with LPS (712, 935). Prostaglandin E2 can readily cross the BBB (183, 224), raising the possibility that PGE2 may enter the brain and stimulate neurosecretory activity in the pPVN. However, although the onset of the increase in blood PGE2 levels was reported to occur simultaneously with the onset of fever after either LPS or IL-1 in the rabbit (712), it is not significantly elevated in the rat until after the peak of the ACTH response to IL-1b has been reached (935). Furthermore, administration of doses of PGE2 that result in blood levels 100- to 400-fold greater than those observed in blood after IL-1b, has a much smaller effect on plasma ACTH concentrations than induced by IL-1b itself (935). Collectively, these data indicate that increased entry of PGE2 into the brain from the systemic circulation is unlikely to be a major intermediary step by which peripheral IL-1 stimulates HPA axis secretory activity. In addition to increased circulating levels of PGE2 , the brain itself represents a potential source of PGE2 in response to peripheral injection of IL-1 or LPS. Both isoforms of COX are present in the brain of normal rats or mice and are expressed predominantly in neurons (100, 104). The patterns of immunostaining for COX-1 and COX2 are distinct and are most prominent in regions of the brain subserving the processing and integration of visceral and special sensory inputs, and in the elaboration of autonomic, endocrine, and behavioral responses (100, 104, 400, 877). In the rat, the PGE2 concentrations in the OVLT, the POAH, PVN, hippocampus, and CSF of the lateral ventricle are all increased within 20 min of intravenous injection of IL-1b (429, 940). All these neuronal structures contain both COX-1 and COX-2 immunoreactivities (100, 104). Ex vivo measurements indicate that mouse hippocampal slices produce more PGE2 after either intraperitoneal or intracerebroventricular treatment with either IL-1a or IL1b (950), whereas in vitro studies have shown that IL-1b and IL-6 increase the release of PGE2 , but not PGF2a , TxB2 , or 6-keto-PGF1a from rat hypothalamic explants (582). Similarly, peripheral administration of LPS in vivo induces increased hypothalamic PGE2 production (789, 799), whereas IL-6 or acute local inflammation increase CSF levels of PGE2 (169, 207). The cellular source of PGE2 in the CNS in response to LPS, turpentine-induced local inflammation, or IL-1 is most likely the cerebrovasculature and/or associated perivascular, structures in which COX2 mRNA is markedly induced by these treatments (140– 11-25-98 11:16:36 pra APS-Phys Rev Downloaded from on April 23, 2014 Eicosanoids are formed by the metabolism of arachidonic acid. The rate-limiting step in the production of eicosanoids is the conversion of arachidonic acid to PGH2 by the enzyme cyclooxygenase (COX; also known as PGH synthase/cyclooxygenase and PG endoperoxide synthase). Two forms of COX have been characterized: a ubiquitously expressed form (COX-1) and a more recently described second form (COX-2) that is induced by various factors including mitogens, hormones, serum, and, of most relevance to this discussion, cytokines (374, 406, 609, 980, 985). Conversion of the resulting PGH2 by specific synthases results in the generation of three eicosanoid families: the prostaglandins (PG), the thromboxanes (Tx), and prostacyclins. The role of PG in the activation of the HPA axis by IL-1 has been particularly well studied largely because of the recognition that PG are critical mediators of IL-1 actions within most peripheral tissues studied (343). Prostaglandins exert effects on HPA axis secretory activity at multiple levels. In the rat, elevated plasma ACTH concentrations are observed within 10 min of intravenous injection of PGE1 , PGE2 , or PGF2a , but not PGD2 (560, 580, 928, 935). Similarly, increases in plasma ACTH concentration are produced by administration of PGE2 directly into the several brain sites, including the preoptic anterior hypothalamus (POAH) (397, 931), the OVLT (397), and the ME (530). Intracerebroventricular administration of PGE2 elicits c-fos mRNA in CRF-containing neurons within the pPVN as well as increased pPVN CRF hnRNA (445). Indeed, PG receptors of the EP-1 subtype (45), but not EP-3 subtype (236, 826), have been demonstrated within the PVN. However, the majority of interest in potential sites of PG action within the CNS has focused on the POAH. Prostaglandin E2 injected into the POAH induces Fos expression in the pPVN (742), and ACTH secretion induced by PGE2 delivered into the POAH can be prevented by prior treatment with an anti-CRF antiserum (931), indicating the importance of activation of hypothalamic CRF secretion. However, in vitro studies investigating the release of CRF from hypothalamic explants have disagreed, with PGE2 being reported to either stimulate or have no effect on CRF secretion (57, 135, 652). Despite the fact that intravenous PGE2 elevates Volume 79 January 1999 REGULATION OF HPA AXIS BY CYTOKINES / 9j0c$$oc11 P13-8 generally accepted to be a critical step in their stimulatory actions on HPA axis secretory activity, the anatomic sites and cell types responsible for PG synthesis are less clear. Two possible sites, the cerebrovasculature and CVO, for which there is substantial evidence that PG play a role in the transduction of a peripheral IL-1 signal into a CNS response are discussed in sections VD and VE. 2. Nitric oxide Nitric oxide is now considered a putative neuromodulator within the mammalian CNS (107, 186, 555). The localization of NO synthase (NOS), the enzyme responsible for NO formation, within the cerebrovasculature and the neuroendocrine hypothalamus (885), the readily diffusible nature of NO, and the proposed role of NO in the mediation of the effects of cytokines (e.g., Refs. 284, 509, 948) provided good evidence for the hypothesis that NO may play a role in the regulation of the HPA axis by cytokines, in a manner akin, or as an adjunct, to PG. However, it appears that during activation of the HPA axis by IL-1 or other inflammatory stimuli, the primary effect of NO is in restraining the HPA axis response (172, 458, 687, 692, 884, 885, 887, 993). The following paragraphs describe the distribution and regulation of NOS within the HPA axis and also the experiments investigating the effects of manipulation of NOS on the HPA axis response to IL-1. Nitric oxide synthase is the enzyme that catalyzes the conversion of L-arginine to L-citrulline and the gaseous mediator NO. Several isoforms of NOS have been identified (265). Nitric oxide synthase I is expressed in the central and peripheral nervous systems and is otherwise known as brain or neuronal NOS. Nitric oxide synthase II is found in many cell types, such as hepatocytes, macrophages, smooth muscle cells, and glia. Finally, NOS III is synonymous with endotheial NOS. These three isoforms are distinct gene products, differ in terms of their pattern of expression (NOS I and III are constitutively expressed, whereas NOS II is present only after induction by cytokines or endotoxin), are either calcium/calmodulin dependent (NOS I and III) or independent (NOS II), and exhibit different kinetic properties. That NO acts as a neuromodulator was first indicated by the demonstration that inhibitors of NOS block the stimulation of cGMP synthesis in brain slices by glutamate acting at NMDA receptors (276). However, NO clearly does not behave like a conventional neurotransmitter, since it is neither stored in nerve terminals nor does it influence its target cell via interaction with a cell-surface receptor. Rather, it diffuses from nerve terminals and forms covalent linkages with several potential postsynaptic intracellular targets (e.g., guanylyl cyclase). Nitric oxide synthase-like activity, NOS immunoreactivity, and NOS mRNA are present within the PVN and SON of the hypothalamus (19, 107, 127, 129, 147, 456, 917– 11-25-98 11:16:36 pra APS-Phys Rev Downloaded from on April 23, 2014 142, 231, 444, 903, 904) (see sect. VD). Microglia (231), neurons (140, 903), meningeal macrophages (231), and astrocytes (652) represent other possible sources of PG in the brain. Inhibitors of COX activity, such as indomethacin or ibuprofen, have been the most commonly used method of investigating the role of PG in HPA axis responses to IL-1. As such, these studies indicate the importance of arachidonic acid metabolites but do not specifically identify PG as the principal players. Peripheral administration of indomethacin abrogates the rise in plasma ACTH concentrations due to intravenous administration of IL-1a, IL-1b, or TNF-a (560, 569, 688, 694, 771, 880, 930). The inhibition observed is not always complete and, in particular, appears to be short-lived, even when indomethacin or ibuprofen is administered several times (C. Rivier, unpublished data). Similar abrogation of IL-1-induced ACTH secretion is produced by indomethacin when IL-1 is injected intracerebroventricular (399, 688, 930) or locally into the ME (530), but results have been inconsistent when IL-1b has been injected intraperitoneally (215, 685). In response to peripheral LPS or local inflammation, administration of COX inhibitors reduces ACTH secretion, an effect that cannot be accounted for by effects of COX inhibition on the inflammation per se (880, 884). Peripheral administration of indomethacin also inhibits the expression of Fos in the pPVN of rats injected intravenously, intraperitoneally, or intracerebroventricularly with either IL-1b or LPS (443, 588, 718, 925) or of rats infused continuously with IL-6 (intravenous) (589). Because indomethacin or ibuprofen can elevate basal GC secretion, it has been suggested that the inhibitory effects of COX inhibitors on cytokine- or inflammationinduced ACTH secretion may be due to enhanced GC feedback. However, a number of lines of evidence indicate that this is probably not the case. For example, elevations of plasma ACTH concentrations produced by either IL-1b (694) or TNF-a (771) in adrenalectomized rats are also abrogated by indomethacin inhibitors, whereas ACTH secretion due to a variety of other stimuli, including intravenous CRF (771, 880), electrofootshock (880), immobilization (399), or insulin-induced hypoglycemia (771), is unaffected by COX inhibition. In vitro studies have also demonstrated that CRF release from hypothalamic explants produced by either IL-1a, IL-1b, or IL-6 is prevented by indomethacin (56, 135, 500, 583). Finally, in addition to the abrogating effects of COX inhibitors on IL-1-induced ACTH secretion, prior intracerebroventricular passive immunoneutralization with antibodies to either PGE1 , PGE2 , or PGF2a also produces a significant reduction in IL-1induced elevations in plasma ACTH (937). Collectively, these data argue for a direct role of PG in the mediation of IL-1 induced activation of the HPA axis. Although the generation of PG in response to IL-1, and a number of other cytokines (e.g., TNF-a, IL-6), is 35 36 ANDREW V. TURNBULL AND CATHERINE L. RIVIER / 9j0c$$oc11 P13-8 tocin (692). These latter findings raise the possibility that increased sensitivity of corticotropes to AVP and/or oxytocin after L-NAME accounts for its potentiation of IL1b-induced ACTH secretion. However, administration of neutralizing antisera to AVP does not influence the exacerbation of IL-1-induced ACTH secretion produced by LNAME (687). Recent studies (887) with partially selective NOS inhibitors identify endothelial (type III) NOS as the most likely source of NO that inhibits the HPA axis response to IL-1b, raising the possibility of functional interactions between NO and IL-1 signaling pathways in cerebrovascular elements (see sect. VD). On the other hand, administration of combined adrenergic antagonists, propanolol and prazosin, partially reverses the effects of LNAME on IL-1-, but not AVP-, induced ACTH secretion (687), suggesting that the inhibitory influence of NO on HPA activity may be due to a suppressive effect on catecholaminergic pathways (see sect. VF). It is interesting to note that the suppressive effect of NO on the HPA axis response to systemic IL-1 has proinflammatory consequences because of the diminution of endogenous GC levels. This proinflammatory neuroendocrine action of NO is in agreement with its local actions as an inflammatory mediator at the site of tissue damage or infection (449). Therefore, NO appears to represent a new class of mediator that belongs to the large families of cytokines, neurotransmitters, and hormones that constitute the common chemical language of the immune and neuroendocrine systems. D. Induction of Intermediates at Blood-Brain Barrier Interface Although there has been much debate as to the precise location of IL-1 receptors within neuronal elements of the brain (see sect. IVA1A), all studies agree that the cerebrovasculature and perivascular elements are the most prominent loci of IL-1R1 mRNA expression in rat or mouse brain (178, 238, 969, 970, 972, 982). Intense signal for IL-1R1 mRNA expression has been described over endothelial cells of the postcapillary venules throughout the entire brain (178, 238, 972, 982), and a number of lines of evidence support a role for such endothelial IL-1 receptors in the transmission of IL-1 signal from blood to brain. Immunoreactive IL-1b is found on the luminal side of endothelial cells lining cerebral venules in rats treated peripherally with LPS (901), whereas increased PGE2 immunostaining has been detected in the cerebral microvasculature after peripheral injection of either IL-1b (904) or LPS (903). Indeed, perivascular elements (probably perivascular microglia) are the major site of COX-2 mRNA induction after systemic treatment with LPS, turpentine, or IL-1 (103, 140–142, 231, 444). Perivascular cells were identified as the primary cell group within the CNS that 11-25-98 11:16:36 pra APS-Phys Rev Downloaded from on April 23, 2014 919). In the pPVN, NOS is found within a subpopulation of CRF-expressing neurons (782, 870). Circumstances known to alter the activity of the pPVN, e.g., immobilization stress (129), intracerebroventricular CRF injection (459), intracerebroventricular IL-1b (459), or systemic LPS treatment (456), upregulate NOS expression in this nucleus, suggesting a role for NO in the regulation of HPA axis. In addition, like the components of the IL-1 system, NOS mRNA is expressed in cerebrovascular elements (969, 974). With regard to localization within the pituitary gland, NOS is found in both the posterior (106, 107) and anterior (148) pituitary. In the anterior pituitary, NOS mRNA and protein are expressed at only low levels in normal animals but are markedly induced by systemic LPS (974). Nitric oxide synthase is also present in the hypophysial portal vasculature (149), which delivers hypothalamic releasing factors to the anterior pituitary. Possible roles of NO in biological processes have been determined using NO donors (L-arginine, nitroprusside), inhibitors of NOS activity (arginine derivatives), and NO scavengers (hemoglobin). Inhibitors of NOS activity are generally low molecular mass (150–500 Da), and the BBB does not appear to hinder their diffusion. These inhibitors have therefore been studied after either systemic or central injection, the latter being chosen when effects on systemic parameters, in particular, blood pressure, were to be avoided. Intravenous pretreatment of rats with the NOS substrate L-arginine blunts the rise in plasma ACTH due to intravenous IL-1b (692). Conversely, the NOS inhibitor NG-nitro-L-arginine methyl ester (L-NAME) (intravenous) exaggerates and prolongs the ACTH and corticosterone responses to IL-1b, an action which is specific to the Lisomer of NAME (the isomer active at NOS), can be reversed by competition with L-arginine, and is unrelated to its hypertensive effects (687, 692, 885, 887). Thus endogenous NO appears to inhibit the ACTH response to systemic IL-1b. Potentiation of ACTH secretion by L-NAME is also observed during responses to turpentine-induced local inflammation and systemic LPS treatment, but interestingly, not to IL-1b administered directly into the brain (intracerebroventricular) (692, 884). The mechanisms by which NO influences the HPA response to IL-1b, inflammation, and endotoxemia are far from clear, but a number of findings have shed some light on likely candidates. Because CRF is an obligatory mediator of the ACTH response to IL-1, a number of in vitro studies have investigated whether NO influences hypothalamic CRF/AVP secretion. However, in hypothalamic explants, NOS inhibitors have been reported to either blunt (116, 724) or exacerbate (172, 993) the increase in CRF/ AVP secretion produced by IL-1. In vivo, L-NAME does not markedly influence ACTH secretion produced by treatment with CRF but potentiates the ACTH response to the two less potent ACTH secretagogues, AVP and oxy- Volume 79 January 1999 REGULATION OF HPA AXIS BY CYTOKINES E. Actions at Circumventricular Organs In addition to cytokine entry into the CNS by way of carrier-mediated transport or diffusion through a disrupted BBB, a number of regions of CNS relatively devoid of a BBB permit cytokine interaction with neuronal elements. These CVO include structures lining the anteroventral border of the third ventricle (AV3V) (namely, the / 9j0c$$oc11 P13-8 OVLT and SFO), the ME, and the AP, posterior lobe of the pituitary, subcommisural organ, and the pineal gland. Their capillaries do not form tight junctions and are thus far more readily penetrable via the paracellular route (305). Circumventricular organs not only contain capillaries with far greater permeability than the rest of the CNS, but the capillary density in these regions is extraordinarily high (369). Penetration of cytokines into brain parenchyma within the CVO does not imply that they may diffuse to interact with deeper brain structures, however, because tight junctions between modified ependymal cells in these regions form a diffusion barrier between CVO and the rest of the brain (369). But these ‘‘leaky’’ sites do provide a means with which cytokines such as IL-1 can influence neuronal activity in these regions of the CNS. The CVO that have been proposed as potential sites of IL-1 action are the structures lining the AV3V region (in particular the OVLT), the ME, and the area postrema, and these are considered further in sections VE1–3. 1. Structures lining the anteroventral border of the third ventricle Substantial evidence has accumulated that the OVLT may serve as an interface between the blood and the brain during the process of an inflammatory response (568, 821). In particular, the role of the OVLT during fever induced by various cytokines or inflammatory stimuli has been well documented, and the OVLT has been proposed as a ‘‘pathway’’ for circulating IL-1 to influence neuronal activity (86, 568, 820, 822). Efferent projections from both the OVLT and the SFO to the PVN provide good anatomic evidence indicating an influence of these structures on the activity of CRF neurosecretory neurons (369, 474, 783). A number of anatomic studies have therefore investigated whether the AV3V region may be a site responsive to the systemic administration of IL-1b. Induction of c-fos mRNA in the OVLT and SFO has been noted within 30–60 min of intraperitoneal injection of IL-1b (98, 187), and Fos protein expression is apparent at 3 h after intravenous IL-1b (237). Similarly, c-fos mRNA has been detected in the OVLT and SFO after intravenous injection of IL-6 (899) and after peripheral injection of LPS (232, 679, 718). The SFO is one of the select regions of the rat brain that displays changes in protein synthesis within 1 h after subcutaneous injection of IL-1b (962), whereas AV3V neurons identified electrophysiologically as projecting to the PVN are responsive to IL-1b within 15 min of its intra-arterial injection (610). Experiments injecting colloidal gold-labeled IL1b (intravenous) into rabbits demonstrated that within 10 min of its intravenous injection, IL-1b is bound to the luminal surface of the endothelium within the OVLT (330). This is followed by internalization of IL-1b and transport to the basal membrane, although IL-1b was not observed 11-25-98 11:16:36 pra APS-Phys Rev Downloaded from on April 23, 2014 express both IL-1R1 and IL-1b-induced cIEG expression 1 h after intravenous injection of IL-1b (238). Finally, IL1R1 expression by perivascular cells, but not neuronal elements, exhibits the expected ligand-induced downregulation after intravenous IL-1b (238). The microvasculature has long been recognized as a target and source of cytokines, with a number of studies focusing specifically on the cerebrovasculature. Such studies have shown that cerebral endothelial cells express cytokine ligands (e.g., IL-1a, IL-1b, IL-6), cytokine-related enzymes (ICE), or receptors (e.g., TNF, IL-1) and are sites of cytokine action (49, 51, 171, 190, 242, 380, 713, 970). Cytokine induction of readily diffusible intermediates, such as NO (412, 969) or PG (77, 78, 201, 904), represents a possible means by which cytokines within the bloodstream can influence cerebral function. A number of in vitro paradigms have been developed to investigate PG formation in the cerebrovasculature. Addition of LPS to isolated feline cerebral microvessels (consisting mainly of capillaries) has been shown to increase their secretion of PGE2 but not 6-keto-PGF1a (77, 78). Studies by Van Dam et al. (904) have demonstrated that cultured rat cerebral endothelial cells (RCEC) bind rat IL1b specifically and express IL-1R1, but not IL-1R2, mRNA. Prostaglandin E2 is the main arachidonic acid metabolite found in rat cerebral endothelial cells (201), and IL-1b increases their secretion of PGE2 and 6-keto-PGF1a , but not TxB2, within 3 h of incubation. As with IL-1b, IL-6 stimulates PGE2 and 6-keto-PGF1a secretion within a period of 3 h (201). Induction of PGE2 secretion through the serosal surface of endothelial cells by luminally confined IL-1 (or possibly other cytokines) represents an extremely plausible means by which IL-1 in the circulation could influence the neuroendocrine hypothalamus. Prostaglandin formation in endothelial/perivascular cells expressing IL-1 receptors within the PVN (178, 982) may provide a relatively local and direct mechanism of HPA axis activation in response to blood-borne IL-1. However, other lines of evidence also indicate that CVO and/or medullary catecholaminergic cell groups are important anatomic structures in mediating the effects of IL-1 on the HPA axis, and there is considerable evidence that PG formation (possibly in perivascular elements) occurs in these regions in response to IL-1. 37 38 ANDREW V. TURNBULL AND CATHERINE L. RIVIER 2. Median eminence The ME contains the terminal projections from CRF secretory neurons arising from the pPVN. Being an area of the hypothalamus that is richly supplied by vasculature relatively devoid of a BBB, the ME is a potential site by which circulating factors can enhance CRF secretion by interacting with pPVN nerve terminals, and stimulating CRF release without directly stimulating CRF cell bodies in the pPVN. Evidence supporting the concept that the / 9j0c$$oc11 P13-8 ME is a primary site of action of circulating IL-1 in the stimulation of CRF secretion derives from a number of experimental findings. For example, microinjection of IL1a, IL-1b, or IL-6 into the ME rapidly stimulates ACTH secretion (525–527, 530, 772). The doses of IL-1 or IL-6 required to elicit increases in plasma ACTH concentration after microinjection into the ME are significantly, although not markedly (2- to 5-fold), less than those required to elicit ACTH after intravenous administration of cytokine. As demonstrated for intravenous or intracerebroventricular injection of IL-1, the plasma ACTH response to intra-ME IL-1b is markedly reduced by indomethacin (530), suggesting the importance of PG formation as an intermediate step. However, in vitro studies attempting to determine whether the enhanced CRF release observed after incubation of hypothalamic explants (which include the ME) can be accounted for by actions on the ME have yielded conflicting data (583, 813, 863). Although intravenous IL-1b induces c-fos mRNA and Fos protein in the PVN at 60–180 min, the observation that intracerebroventricular and intravenous injection of doses of IL-1b elicit differential c-fos mRNA expression in the PVN at 30 min suggested that the ME may be the primary target after intravenous IL-1b (684). This conclusion was based on the fact that both routes of IL-1b administration rapidly stimulate ACTH secretion, yet c-fos mRNA in the pPVN 30 min after IL-1b was observed only after intracerebroventricular IL-1b. This suggests that pPVN cell bodies represent an early target of IL-1b after its intracerebroventricular, but not intravenous, administration. Because both routes of IL-1b administration elicit rapid (within minutes) increases in CRF secretion, it seemed likely that IL-1b administered intravenously acts at the level of the ME (684). However, subsequent neuroanatomic data supporting this hypothesis are not strong. In situ histochemical studies have described the expression of IL-1R1 mRNA in the rat ME to be either weak (982) or absent (238, 972), whereas in the mouse, only labeling on ‘‘scattered cells’’ is apparent (178). Radioligand binding studies have similarly shown either low (251) or no (516) signal within the rat ME and no specific signal in the mouse ME (30, 848). Indeed, although LPS induces c-fos mRNA in several layers of the ME (679), cfos mRNA or Fos protein induction has not been observed in the ME in response to systemic IL-1b (98, 187, 237, 588). 3. Area postrema Recent studies implicated the AP in the mediation of HPA activation in response to IL-1b administered intravenously (238). Whereas other CVO do not contain IL-1 receptors to any appreciable extent (at least in neuronal elements), the AP was shown to contain positive hybridization signal for IL-1R1 mRNA, although the cell type 11-25-98 11:16:36 pra APS-Phys Rev Downloaded from on April 23, 2014 in the neighboring POAH (330). In addition to being responsive to IL-1b, the AV3V regions have been demonstrated to be a site of production of IL-1b in response to systemic treatment with LPS (see sect. IVA2B). Consistent with a role for the AV3V in mediating the effects of systemic IL-1b action on the HPA axis, placement of either radiofrequency or kainic acid-induced lesions in the OVLT markedly reduces ACTH secretion in response to intravenous IL-1b, but not immobilization stress (397). However, there is little or no evidence for the existence of IL-1 receptors within neuronal elements within the AV3V. With the consideration of the density of vasculature in this region and the demonstration of IL-1 receptors on endothelial and perivascular cells, these may well represent the cellular targets of IL-1b within the AV3V. Consistent with the idea of PG formation being the principal action of IL-1b in the AV3V, enhanced PGE2 formation in this region has been noted after systemic treatment with IL-1b or LPS (429, 903, 940). Furthermore, microinjection of indomethacin into the OVLT markedly attenuates the rise in plasma ACTH concentrations due to IL-1b (397). That adjacent neuroanatomic structures such as the POAH represent the target of PG action is supported by a number of observations. The POAH (but not the OVLT itself) contains a high density of PGE2 binding sites (523, 524, 933, 934), mRNA for the PG receptor EP-3 (236, 826), and the plasma ACTH response to intravenous IL-1b is inhibited by either electrolytic or kainic acidinduced lesions of the POAH or by microinjection of a PG antagonist into this brain region (397). Although there is substantial evidence that the AV3V, and in particular the OVLT, may serve as an neuroanatomic site of action of circulating IL-1b, none of the experiments investigating the effects of either surgical or pharmacological manipulation of the OVLT showed complete inhibition of the plasma ACTH response to IL-1b (397). Furthermore, the dose of IL-1b used in these studies was extremely high (10 mg/kg iv). In more recent dose-response studies, the minimum dose of IL-1b required to induce Fos protein in the OVLT (3.58 mg/kg) was found to be Ç10-fold higher than that required to stimulate Fos expression in the pPVN (237), suggesting that the involvement of the OVLT in the HPA axis response to systemic IL-1b may be restricted to high circulating levels of IL-1b. Volume 79 January 1999 REGULATION OF HPA AXIS BY CYTOKINES expressing IL-1R1 could not be identified. Most importantly, the AP is the only CVO that reliably displays intravenous IL-1b-induced cIEG expression (237, 238). However, ablation of the AP does not influence IL-1b-induced CRF mRNA or Fos expression within the PVN (235), suggesting that it is not a critical relay site in the activation of the hypothalamic PVN in response to IL-1b. F. Potential Role of Catecholamines and Evidence of Activation of Medullary Cell Groups / 9j0c$$oc11 P13-8 medullary catecholaminergic fibers (using 6-hydroxydopamine) consistently produce a marked depletion of hypothalamic NE concentrations and inhibit the plasma ACTH or corticosterone response to intracerebroventricular or intraperitoneal IL-1b (160, 949). A similar inhibitory effect has been noted when 6-hydroxydopamine is infused into the lateral ventricle (526, 949) or directly into the PVN (160). Discrete lesions of ascending catecholaminergic inputs to the hypothalamus (affecting either dorsal, ventral or intermediate axons) showed that the plasma ACTH responses to either intra-arterial IL-1b or LPS, or intraPVN IL-1b, is dictated by brain stem catecholaminergic input to the hypothalamus and that the effect of lesion was dependent on the route of cytokine administration and precise location of the lesion (39, 291). Recent studies have provided even more substantial evidence for the critical role of medullary catecholaminergic innervation of the hypothalamus in the activation of the HPA axis in response to systemic IL-1. Administration of IL-1b, either intravenously or intraperitoneally, results in marked expression of c-fos mRNA or Fos protein in the NTS of the rat (98, 187, 237). Similarly, all studies investigating the CNS distribution of either Fos protein of c-fos mRNA in response to systemic LPS have noted induction of this early-immediate gene expression in (likely catecholaminergic) medullary cell groups within 1–3 h of LPS injection (230, 232, 678, 679, 718, 924). Ericsson et al. (237) described Fos protein expression throughout the rostrocaudal extent of the medial and commisural nuclei of the NTS, as well as in the rostral ventrolateral medulla and in the dorsal motor nucleus of the vagus within 3 h of intravenous IL-1b. These authors demonstrated that Fos expression in the NTS is very sensitive to IL-1b and is induced at doses lower than those required to elicit a specific signal within the pPVN. Retrograde tracing studies indicated that the NTS and rostral ventrolateral medulla are the sources of projections to the PVN that most consistently express IL-1b-induced Fos protein (237). The majority of these projections are catecholaminergic (237). Furthermore, unilateral surgical disruption of ascending catecholaminergic projections from the medulla to the PVN prevents intravenous IL-1b-induced expression of Fos protein and CRF mRNA in the ipsilateral, but not contralateral, pPVN (237, 468). Finally, although such a surgical disruption of medullary-PVN fibers does not prove a catecholaminergic involvement, a recent study demonstrated that 6-hydroxydopamine lesions also substantially reduce intraperitoneal IL-1b-induced Fos expression in the PVN of the mouse (831). The activation of medullary catecholaminergic cell groups seems unlikely to be because of a direct activation by IL-1, since these cell groups do not express IL-1R1 mRNA (238). Given the demonstrated critical role of PG in the HPA axis response to IL-1 (see sects. VC1 and VD), it is not surprising that there has been considerable inter- 11-25-98 11:16:36 pra APS-Phys Rev Downloaded from on April 23, 2014 In addition to PG, there is a second class of intermediates for which there exists substantial evidence in the mediation of IL-1-induced activation of the HPA axis, namely, monoamines. Monoamine utilization and/or content in the hypothalamus and other regions of the CNS is altered by immunologic challenges, such as those produced by inoculation with sheep red blood cells (69, 767, 997), NDV (220, 221), Poly I:C (221), and influenza virus (219) and by peripheral administration of LPS (193, 212, 222, 450, 478). Intraperitoneal administration of either IL1a or IL-1b to mice also elevates cerebral metabolism of norepinephrine (NE) and serotonin, with effects being most marked in the hypothalamus (211, 222). Similarly, intravenous or intraperitoneal IL-1b increases NE turnover in the hypothalamus (including PVN) as well as other regions of the rat brain (386, 553, 790). Intrahypothalamic or intracerebroventricular infusion of IL-1b also modulates hypothalamic monoamine levels (554, 773, 776, 860). As for other cytokines, intraperitoneal injection of IL-2 increases hypothalamic NE turnover in mice (996), and peripheral administration of IL-6 produces either small (222) or no increases (213, 858, 996) in hypothalamic NE and serotonin turnover. Intraperitoneal TNF-a was found to have no effect on hypothalamic NE turnover in mice (213) or rats (858) but was reported to inhibit NE release from the isolated ME in vitro (226). There is extensive evidence that noradrenergic innervation of the hypothalamus influences the secretion of CRF from the hypothalamus (reviewed in Refs. 9, 649, 727, 739, 833). The PVN and SON represent two of the most prominent terminal fields of catecholaminergic neurons. These projections derive from medullary cell groups, in particular the NTS. Noradrenergic and adrenergic neurons from the rostral and caudal regions of the NTS project preferentially to the pPVN, as does the major projection field of the NTS, the C1 adrenergic cell group (739). Lesion of pathways from medullary catecholaminergic cell groups to the PVN has been reported to disrupt HPA axis responses to diverse stimuli (181, 832). The use of adrenergic receptor antagonists to explore the role of catecholamines in IL-1-induced activation of the HPA axis has produced inconsistent data (134, 695, 949). On the other hand, neurotoxic lesions of ascending 39 40 ANDREW V. TURNBULL AND CATHERINE L. RIVIER G. Activation of Vagal Afferent Fibers Studies over the last few years have indicated a novel route through which peripheral cytokines may influence the CNS without gaining access to brain parenchyma, the BBB interface, or even the systemic circulation. In 1994, Nance and co-workers (925) demonstrated that the induction of Fos protein in the PVN and SON of the hypothalamus produced by an intraperitoneal injection of LPS is prevented by surgical subdiaphragmatic transection of the vagus (SDVX) several days before LPS administration (925). At a similar time, Dantzer and co-workers (90) showed that SDVX reduces sickness behavior after intraperitoneal LPS, whereas Watkins et al. (944) reported that hyperalgesia produced by intraperitoneal LPS is also reduced by prior sectioning of the vagus (944). These data suggested that the vagus is a neural afferent route by which inflammation within the peritoneal cavity can influence the brain. A number of independent laboratories have now confirmed the existence of such a mechanism in rats, mice, and guinea pigs. The SDVX procedure reduces fever (297, 389, 607, 701, 761), sleep (389, 607), NE turnover (359), food-motivated sickness behavior (90, 108, / 9j0c$$oc11 P13-8 451), and the elevation of hypothalamic IL-1b mRNA (451) induced by the administration of LPS into the abdominal/ peritoneal cavity. Dantzer and co-workers (90, 451) demonstrated that the inhibitory effect of SDVX on CNS-mediated responses to intraperitoneal LPS was not due to a reduced peripheral inflammatory response, since LPS-induced expression of cytokines in tissues other than the brain is unaffected by SDVX (90, 451). This suggests that it is the transduction of a cytokine signal to the brain that is impaired in SDVX animals. Indeed, it has now been shown that the fever (607, 942), increased sleep (319), NE turnover (261), hyperalgesia (945), behavioral effects (88, 89, 294), and induction of IL-1b mRNA in the CNS (320) produced by intraperitoneal IL-1 are all diminished or absent in SDVX animals. Similarly, SDVX inhibits hyperalgesia and conditioned taste aversion induced by intraperitoneal TNF-a (294, 941). Although SDVX inhibits CNS-mediated effects of intraperitoneal TNF-a (e.g., hyperalgesia, activation of the HPA axis), ‘‘peripheral organ’’ effects (e.g., reduction of glucocorticoid binding globulin) are unaffected by this surgical procedure (262), suggesting that the role of the vagus is specific to CNS-mediated acute phase responses. The vagus also appears to play a role in the activation of the HPA axis in response to peripheral LPS or cytokine. In rats, SDVX attenuates the rise in plasma ACTH and corticosterone concentrations produced by intraperitoneal IL-1b (261, 390). The number of CRF containing neurons in the pPVN that stain positive for Fos and the rise in plasma ACTH concentration produced by LPS are likewise attenuated in SDVX animals (279), indicating that vagotomy interferes with the activating signal to the neuroendocrine hypothalamus. Similarly, SDVX blocks the rise in plasma corticosterone caused by intraperitoneal TNF-a (262). A number of studies have addressed the question of how SDVX interferes with the generation of CNS-mediated acute phase responses to either LPS or IL-1. The SDVX procedure is a major surgical intervention resulting in SDVX animals being less ‘‘healthy’’ than sham-operated or control rats. It has been suggested that the inability of SDVX rats to respond normally to inflammatory stimuli may relate to their overall health status rather than to a specific effect of SDVX on ‘‘immune-to-brain’’ communication. However, even in SDVX rats receiving special perioperative care to prevent malnutrition, the febrile response to intraperitoneal LPS is still impaired (699). In addition, SDVX animals respond with elevations in body temperature (543, 700), hyperalgesia (941), and activation of the HPA axis (390, 943) in a manner similar to sham-operated animals when the stimulus is not an inflammatory one (e.g., insulin- or electrofootshock-induced elevations in plasma ACTH concentrations). Although the importance of vagal afferents in the mediation of CNS-mediated acute phase responses to abdom- 11-25-98 11:16:36 pra APS-Phys Rev Downloaded from on April 23, 2014 est in the possibility that PG are an important intermediary between IL-1 action and activation of medullary catecholaminergic neurons. Accordingly, the induction of medullary Fos protein (235) and the changes in hypothalamic monoamine turnover (534, 857, 858, 860) produced by IL-1 have been shown to be prevented by COX inhibitors. Indeed, the PG receptor subtype EP-3 is present in the NTS and ventrolateral medulla, in which IL-1-sensitive catecholamine neurons reside (236). Furthermore, the administration of PGE2 into the rostral ventrolateral medulla provokes a pattern of Fos expression in hypothalmic nuclei (including the pPVN) that closely resembles that produced by intravenous IL-1b (235). These observations have led to the conclusion that PGE2 released from perivascular cells in the medulla as a consequence of IL-1 stimulation activates local catecholaminergic neurons that project to the PVN (235). In addition to a role in the activation of the HPA axis produced by IL-1 interacting with neuronal and/or cerebrovascular elements within the brain, a further importance of medullary catecholaminergic cell groups in the mediation of cerebral influence of peripheral IL-1 has recently become apparent. Medullary cell groups play an important role in the processing of visceral sensory information carried by sensory components of the vagus and glossopharyngeal nerves (739). Recent evidence that an intact vagus is critical to elaboration of CNS responses to abdominal/peritoneal inflammation (see sect. VG) suggests that medullary cell groups may receive information regarding the localized peripheral activity of IL-1 (238). Volume 79 January 1999 REGULATION OF HPA AXIS BY CYTOKINES H. Cytokine Synthesis Within Brain The previous discussions focussed on answering the question of how IL-1 generated within the periphery may signal the brain to elicit HPA activation. Recent studies have demonstrated that IL-1, as well as other cytokines, are also generated within the brain (see sect. IVA2), thus raising the question of whether such brain-derived IL-1 may influence HPA axis secretory activity. The present data regarding the distribution of IL-1 receptors within the brain would seem to argue against a role for cerebral / 9j0c$$oc11 P13-8 IL-1 in regulating the activity of the neuroendocrine hypothalamus, since IL-1 receptors are located predominantly in barrier-related regions (e.g., perivascular elements) suited to transducing an IL-1 signal from blood to the brain, but not to mediating effects of IL-1 generated within brain. The only hypothalamic nucleus that expresses IL1 receptors on neuronal elements is the arcuate nucleus, which is known to influence HPA axis secretory activity (238), but whose role in mediating the effects of IL-1 has not been determined. Despite a lack of evidence for an action of cerebral IL-1 on HPA axis secretory activity based on the distribution of IL-1 receptors within the brain parenchyma, IL-1 administered directly into the brain induces Fos expression in the pPVN, elevates PVN CRF mRNA, enhances CRF secretion from the ME, and increases plasma concentrations of ACTH and corticosterone (see sect. IVA3). Furthermore, the doses of IL-1 needed to stimulate HPA axis secretory activity are lower than those required when the cytokine is administered peripherally, clearly indicating a CNS site of action of cerebrally administered IL-1. Finally, incubation of the hypothalamus with IL-1 in vitro elicits CRF secretion (see sect. IVA3). Collectively, these data argue strongly that when CNS production of IL-1 is increased it is likely to stimulate HPA axis secretory activity. Pathologies comprising direct cellular insults (infection, trauma, ischemia, and disease) to the CNS clearly induce the synthesis of IL-1 and other cytokines within the brain. However, only very few studies have investigated cytokine regulation of the HPA axis during such pathologies, although the work performed has implicated brainderived IL-1 in the activation of the HPA axis in response to CNS viral disease. For example, intracerebral infusion or transgenic expression of gp120, the envelope protein of the human immunodeficiency virus, causes an increase in brain IL-1 biological activity and mRNA and elevates plasma ACTH and corticosterone concentrations (112, 355, 657, 661, 827). Coinfusion of a-melanocyte-stimulating hormone (which inhibits IL-1 actions, but not synthesis) completely prevents the elevation in plasma corticosterone concentrations, suggesting that IL-1 generated in brain as a consequence of gp120 infusion produces activation of the HPA axis (827). Similarly, induction of IL-1b within the brain has been proposed as the mechanism responsible for increased adrenocortical activity in rats inoculated with the neurotropic herpes simplex virus-1 (50). Many studies have begun to address a question of much broader significance to the concept to neuroimmune regulation, i.e., whether events unrelated to direct cellular insults to the CNS can induce the synthesis within the brain of cytokines, which subsequently regulate CNS activity, and play a physiological role in orchestrating adaptive responses. In particular, work has focused on the possibility that an immune/inflammatory response 11-25-98 11:16:36 pra APS-Phys Rev Downloaded from on April 23, 2014 inal inflammation is not undisputed (e.g., Ref. 755), the weight of evidence supporting this hypothesis is now substantial, and a number of studies have begun to unravel how cytokines might interact with the vagus. Administration of IL-1 into the hepatic portal vein produces increased electrical activity of the hepatic branch of the vagus (586, 587), suggesting the possible importance of this vagal branch. However, in contrast to SDVX, selective sectioning of the hepatic vagus does not inhibit the rise in either plasma corticosterone or hypothalamic NE turnover in response to intraperitoneal IL-1 (261), or the suppression of food intake in response to LPS (447). Similarly, the hypothesis that C-fiber afferents are the principal vagal fiber type important in the vagal signal to the brain has been disproven (109). What does seem clear at the present time is that while abdominal vagal afferents themselves do not appear to contain functional IL-1 receptors, abdominal paraganglia, which are in close proximity to and synapse with vagal fibers, bind biotinylated IL-1ra specifically (296). Furthermore, macrophages are found close to vagal fibers and paraganglia after treatment with LPS (295), suggesting a close association between IL-1producing cell types, IL-1 receptors, and abdominal vagal afferents. The vagus appears to be important in signaling the brain specifically during intra-abdominal/peritoneal inflammation. This is evidenced by the lack of effect of SDVX on CNS-mediated acute phase responses, such as activation of the HPA axis (235, 399), when either IL-1 or LPS is administered via routes other than into the abdomen/peritoneum (88, 89, 235, 297, 399, 645). However, global depletion of C-fiber afferents (by repeated systemic treatment with capsaicin during adulthood) inhibits the plasma ACTH response to intravenous IL-1b (932). Furthermore, the initial (within 45 min) rise in plasma ACTH concentrations produced by intramuscular turpentine is reduced in rats treated neonatally with capsaicin (879). Therefore, it seems possible that sensory fibers, other than vagal abdominal/peritoneal afferents (e.g., from skin or muscle), are capable of signaling the brain of the occurrence of high local concentrations of cytokines in the periphery. 41 42 ANDREW V. TURNBULL AND CATHERINE L. RIVIER / 9j0c$$oc11 P13-8 LPS (2.5 mg ip). These authors simultaneously measured the quantities of human IL-1ra that escaped into the general circulation and in separate experiments demonstrated that these levels in plasma had no effect on the increase in CRF mRNA in response to LPS. Therefore, it would appear that IL-1 acts within the brain to stimulate the increase in CRF mRNA in response to peripheral LPS, although concomitant plasma ACTH levels were not measured. However, whether or not the IL-1 responsible for elevating CRF mRNA was of CNS rather than peripheral origin can still not be assumed. We also found evidence indicating that TNF-a may act within the brain to activate the HPA axis in response to local inflammation. The intracerebroventricular, but not intravenous, administration of either 5 ml anti-TNF-a antiserum or 1–50 mg of a soluble TNF receptor construct inhibits the second rise in plasma ACTH concentrations produced by intramuscular turpentine (881). Because no increases in plasma TNF-a are apparent during discrete, localized inflammation, we assumed that TNF-a not only acted within the brain but that the CNS was the major source of TNF-a. However, we found no evidence of elevated TNF-a, IL-1, or IL-6 synthesis within the rat brain, as assessed by in situ hybridization histochemistry or semiquantitative PCR. Whether increased release of prestored TNF-a (105) or synergistic actions of TNF-a with PG (whose levels in the brain are elevated) (256) accounts for these observations is not known. Surprisingly, more convincing evidence that IL-1 generated within the CNS plays a role in stimulating HPA axis secretory activity comes from studies investigating the neuroendocrine responses to immobilization stress (546, 777, 778). Minami et al. (546) reported that IL-1b mRNA expression was induced in the rat hypothalamus within 30 min of the commencement of immobilization stress. Interleukin-1b mRNA peaked at 60 min and was still elevated at 120 min. These results are particularly surprising given that these authors detected IL-1b mRNA using Northern blot hybridization, whereas the more sensitive technique of RT-PCR has been required to reliably demonstrate increases CNS expression of IL-1b mRNA in response to systemic LPS. Nonetheless, this group subsequently reported increases in hypothalamic IL-1 biological activity within 30–60 min of immobilization stress and furthermore demonstrated that microinjection of IL-1ra (2 mg) into the hypothalamus inhibits the stress-induced rise in plasma ACTH concentrations by as much as 50% (778). On the other hand, we have found no significant effects of either IL-1ra (100 mg icv) or anti-TNF-a antiserum on the rise in plasma ACTH concentrations produced by electrofootshock in rats (Ref. 881 and unpublished data), whereas others (716) have found that IL-6 deficiency does not influence the HPA axis response to immobilization in mice. These data would seem to indicate that the participation of cytokines in psychological/physical 11-25-98 11:16:36 pra APS-Phys Rev Downloaded from on April 23, 2014 within the periphery is paralleled by, or even initiates, cytokine production within the CNS. As detailed in section IVA2B, the peripheral administration of LPS has been shown to induce cytokine and, in particular, IL-1 synthesis within the brain. However, by far the majority of studies which investigated cellular localization of cytokines demonstrated that IL-1 mRNA and protein are only induced within brain parenchyma at doses (hundreds of micrograms to milligrams) well above those required to observe physiological responses such as activation of the HPA axis (õ1 mg/kg). Furthermore, cytokine induction within brain parenchyma is observed only several hours after LPS administration (compare increases in ACTH secretion at 30–45 min). Indeed, the location of IL-1 mRNA and protein that is induced fastest and at lowest doses appears to be in barrier-related regions such as the CVO and perivascular sites, suggesting a site of action on the blood side of the BBB. Therefore, cytokine synthesis within brain parenchyma would appear not to be an absolute requirement for at least those responses that occur rapidly after LPS administration. Nevertheless, studies have demonstrated that inhibition of IL-1 action within the brain by intracerebral administration of anti-IL-1b antibodies can inhibit acute phase responses to peripheral LPS (418, 709). However, such experiments failed to demonstrate that the IL-1b inhibited is generated within the brain and does not enter from the periphery (see section VB) and also have not necessarily indicated that the site of action of the injected antibodies is within the brain. We have recently found that pretreatment of rats intracerebroventricularly with an anti-TNFa antiserum delays the onset of the rise in plasma ACTH concentrations produced by intravenous injection of 5 mg/ kg LPS, suggesting an action of TNF-a within the brain (889). However, intravenous administration of the same volume of antiserum produced qualitatively and quantitatively the same effect as that observed with intracerebroventricular anti-TNF-a (889). Subsequent studies indicated that antisera rapidly dissipate to the periphery after intracerebroventricular injection and can produce immunoneutralizing concentrations within the periphery within only a very short time period (Ç1–4 h) (890). Experiments using injections of antisera/antibodies or receptor antagonists to inhibit the action of cytokines within the brain clearly need to demonstrate that effects observed cannot be accounted for by actions of the inhibitors in the periphery, particularly given the high concentrations of cytokines that can occur in blood and peripheral tissues during inflammation/infection. One tightly controlled study has indicated that IL-1 may well act within the brain to stimulate HPA axis activation in response to peripheral administration of LPS (387). Kakucska et al. (387) demonstrated that continuous intracerebroventricular infusion of human IL-1ra completely prevents the rise in pPVN CRF mRNA observed 8 h after Volume 79 January 1999 REGULATION OF HPA AXIS BY CYTOKINES 43 stress-induced HPA activation is probably limited to specific cytokines and specific stressors. Overall, although there is substantial evidence that IL-1 can be produced in the brain during CNS insults, severe endotoxemia, and possibly also acute physical/psychological stress, there is only limited data implicating CNS-derived IL-1 in the regulation of the associated HPA axis secretory responses. Direct testing of the physiological role of CNS-derived cytokines in the regulation of the HPA axis awaits the development of appropriate genetargeting strategies that selectively mutate cytokine synthesis in a region- or cell type-specific manner (875). / 9j0c$$oc11 P13-8 11-25-98 11:16:36 pra APS-Phys Rev Downloaded from on April 23, 2014 tions can be observed within 5–10 min of IL-1 administration. However, there is evidence that IL-1 administered intraperitoneally stimulates ACTH secretion in the mouse in an IL-6-dependent fashion (584, 640). It is unfortunate, therefore, that given the much higher incidence of high levels of IL-6 rather than IL-1 during pathophysiological states, there is a relative paucity of information regarding the mechanisms of activation of the HPA axis in response to exogenous IL-6 than there is in response to exogenous IL-1 (see sects. VA– VH). At least part of the reason why this is the case is because of the relative impotency of IL-6 compared with IL-1 when these cytokines have been administered to animals (66, 527, 909, 1003). Whether this reflects a true difference in the potencies of the two cytoI. Local Interleukin-1 Induction of Circulating kines to interact with components of the HPA axis, or Interleukin-6 reflects the fact that IL-1 also induces prolonged high circulating levels of IL-6, is not presently known. Nevertheless, it Finally, it seems pertinent to consider the possibility is clearly important to determine whether the mechanisms that IL-1 induced by peripheral infection/inflammation can described above for IL-1 are also relevant for, or are in fact activate the HPA axis by a mechanism that does not in- mediated by, IL-6. Such future studies would clearly benefit volve a ‘‘direct’’ interaction of IL-1 with any of the above from the use of infusions of IL-6 to mimic the levels of mechanisms. There is substantial evidence that the effect IL-6 actually observed during pathological conditions. of IL-1 on the HPA axis during peripheral infection/inflammation is mediated via the induction of high circulating levels of IL-6 and that it is IL-6 that actually interacts VI. CONCLUSIONS with components of the HPA axis. Indeed, IL-1 potently stimulates the synthesis and secretion of IL-6 (e.g., Refs. The landmark discoveries of Besedovsky’s and Bla470, 585, 766, 871). Studies of the HPA axis response to lock’s groups culminated with their demonstrations that viral infection (MCMV; see sect. IIIA3) clearly indicate IL-1 is an important endogenous regulator of the HPA that systemic administration of IL-1ra inhibits the rise in axis. Since that time, a tremendous growth in the study plasma corticosterone levels (716). Because IL-1b was of cytokine biology has provided several major advanceundetectable in the general circulation, plasma IL-1a con- ments in the understanding of immune-neuroendocrine centrations were not elevated during MCMV, and the interactions. First, we now know that, in addition to ILmarked rise in plasma IL-6 levels was reduced by ú75% 1, numerous other cytokines are capable of influencing by treatment with IL-1ra, the authors concluded that IL-6 HPA secretory axis activity, with most having a stimulais a circulating mediator of IL-1 actions (716). Indeed, they tory action. Cytokine receptors have been cloned, characshowed that IL-6-deficient mice also display a markedly terized, and localized to many neuroendocrine (among reduced corticosterone response to MCMV (716). Simi- other) tissues. Furthermore, it is now recognized that the larly, turpentine-induced local inflammation induces ele- HPA axis exposure to cytokines is not restricted to those vated levels of IL-1b locally but not systemically, IL-1 is carried within the vascular supply, since the CNS, pituresponsible for inducing high circulating levels of IL-6 in itary, and adrenal are all capable of synthesizing a variety plasma, and IL-6-deficient mice display a markedly re- of cytokines, whose levels are increased during endotoxeduced HPA axis response (see sect. IIIC). Such studies mia. Furthermore, neural afferents, such as those carried strongly suggest that circulating IL-6 may mediate the ef- within the vagus nerve, may be a target of cytokine action fects on the HPA axis of locally increased levels of IL-1. that conveys information from inflammatory sites to the Indeed, IL-6 has been suggested to mediate a number of brain. Finally, recent studies suggesting that cytokine regother IL-1 actions, including inhibition of proteoglycan ulation of the HPA axis may occur not only during infecsynthesis in cartilage, induction of thymocyte prolifera- tion, inflammation, and trauma, but also during periods tion, and the production of fever (97, 150, 333, 585, 602). of psychological and/or physical stress unrelated to the Therefore, there is substantial evidence that during patho- presence of tissue disease or damage, have given a new physiological circumstances IL-6 may well be a major me- perspective on the nature of immune-neuroendocrine indiator of IL-1 action. teractions. It seems unlikely that intravenous administration of Clearly, the pituitary and adrenal glands represent exogenous IL-1 results in an IL-6-dependent activation of potential targets of cytokine action on the HPA axis when the HPA axis, since elevations of plasma ACTH concentra- these organs are exposed to prolonged elevated cytokine 44 ANDREW V. TURNBULL AND CATHERINE L. RIVIER We thank Dr. Steve Hopkins for helpful discussions during the preparation of this manuscript. Research in the authors’ laboratories was supported by National Institutes of Health Grants DK-26741 and MH-51774, the Foundation for Research Inc., Aaron and Amoco Fellowships, and the British Medical Research Council. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. REFERENCES 1. ABRAHAM, E. J., AND J. E. MINTON. Cytokines in the hypophysis: a comparative look at interleukin-6 in the porcine anterior pitu- / 9j0c$$oc11 P13-8 19. 11-25-98 11:16:36 itary gland. Comp. Biochem. Physiol. A Physiol. 116: 203–207, 1997. ADASHI, E. Y. The potential role of IL-1 in the ovulatory process: an evolving hypothesis. J. Reprod. Immunol. 35: 1–9, 1997. ADDISON, T. On the Constitutional and Local Effects of the Suprarenal Capsules. London: Highley, 1855. AGUADO, F., J. RODRIGO, L. CACICEDO, AND B. MELLSTROM. Distribution of insulin like growth factor-I receptor mRNA in rat brain. Regulation in the hypothalamo-neurohypophysial system. J. Mol. Endocrinol. 11: 231–239, 1993. AKITA, S., P. M. CONN, AND S. MELMED. Leukemia inhibitory factor (LIF) induces acute adrenocorticotrophic hormone (ACTH) secretion in fetal rhesus macaque primates: a novel dynamic test of pituitary function. J. Clin. Endocrinol. Metab. 81: 4170–4173, 1996. AKITA, S., J. MALKIN, AND S. MELMED. Disrupted murine leukemia inhibitory factor (LIF) gene attenuates adrenocorticotropic hormone (ACTH) secretion. Endocrinology 137: 3140–3143, 1996. AKITA, S., J. WEBSTER, S. G. REN, H. TAKINO, J. SAID, O. ZAND, AND S. MELMED. Human and murine pituitary expression of leukemia inhibitory factor. Novel intrapituitary regulation of adrenocorticotropin hormone synthesis and secretion. J. Clin. Invest. 95: 1288–1298, 1995. AKIYAMA, H., T. NISHIMURA, H. KONDO, K. IKEDA, Y. HAYASHI, AND P. L. MCGEER. Expression of the receptor for macrophage colony stimulating factor by brain microglia and its upreguation in brains of patients with Alzheimer’s disease and amyotropic lateral sclerosis. Brain Res. 639: 171–174, 1994. AL-DAMLUGI, S. Adrenergic mechanisms in the control of corticotrophin secretion. J. Endocrinol. 119: 5–14, 1988. ALHEIM, K., Z. CHAI, G. FANTUZZI, H. HASANVAN, D. MALINOWSKY, E. DI SANTO, P. GHEZZI, C. A. DINARELLO, AND T. BARTFAI. Hyperresponsive febrile reactions to interleukin (IL) 1a and IL-1b and altered brain cytokine mRNA and serum cytokine levels, in IL-1b-deficient mice. Proc. Natl. Acad. Sci. USA 94: 2681–2686, 1997. ALLAERTS, W., P. H. M. JEUCEN, R. DEBETS, S. HOEFAKKER, AND E. CLAASSEN. Heterogeneity of pituitary folliculo-stellate cells: implications for interleukin-6 production and accessory function in vitro. J. Neuroendocrinol. 9: 43–53, 1997. ALOISI, F., A. CARE, G. BORSELLINO, P. GALLO, S. ROSA, A. BASSANI, A. CABIBBO, U. TESTA, G. LEVI, AND C. PESCHLE. Production of hemolymphopoietic cytokines (IL-6, IL-8, colony stimulating factors) by normal human astrocytes in response to IL-1b and tumor necrosis factor-a. J. Immunol. 149: 2358–2366, 1992. AMANO, O., Y. YOSHITAKE, K. NISHIKAWA, AND S. ISEKI. Immunocytochemical localization of basic fibroblast growth factor in the rat pituitary gland. Arch. Histol. Cytol. 56: 269–276, 1993. ANDREIS, P. G., G. NERI, A. S. BELLONI, G. MAZZAOCHI, A. KASPRZAK, AND G. NUSSDORFER. Interleukin-1b enhances corticosterone secretion by acting directly on the rat adrenal gland. Endocrinology 129: 53–57, 1991. ANTONI, F. A., G. FINK, AND W. J. SHERWOOD. Corticotropinreleasing peptides in rat hypophysial portal blood after paraventricular nucleus lesions: a marked reduction in the concentration of corticotropin-releasing factor-41, but no change in vasopressin. J. Endocrinol. 125: 175–183, 1990. APPEL, K., M. BUTTINI, A. SAUTER, AND P. J. GEBICKEHAERTER. Cloning of rat interleukin-3 receptor beta-subunit from cultured microglia and its mRNA expression in vivo. J. Neurosci. 15: 5800–5809, 1995. ARANGUEZ, I., C. TORRES, AND N. RUBIO. The receptor for tumor necrosis factor on murine astrocytes: characterization, intracellular degradation, and regulation by cytokines and Theiler’s murine encephalomyelitis virus. Glia 13: 185–194, 1995. ARAUJO, D. M., P. A. LAPCHAK, B. COLLIER, AND R. QUIRION. Localization of interleukin-2 immunoreactivty and interleukin-2 receptors in the rat brain: interaction with the cholinergic system. Brain Res. 498: 257–266, 1989. AREVALO, R., F. SANCHEZ, J. R. ALONSO, J. CARRETERO, R. VAZQUEZ, AND J. AIJON. NADPH-diaphorase activity in the hypo- pra APS-Phys Rev Downloaded from on April 23, 2014 levels. However, the majority of evidence indicates that either direct or indirect stimulation of hypothalamic CRF secretion is the primary means by which cytokines (at least IL-1, IL-6, and TNF-a) activate the HPA axis. The neuroanatomic and neuropharmacological pathways by which IL-1 has been proposed to influence the neuroendocrine hypothalamus are numerous and diverse. Accurate models of the mechanisms by which IL-1 activates the HPA axis have to take into account the consistently reported inhibitory effects of either inhibitors of PG synthesis or disruption of catecholaminergic input into the hypothalamus. In the situation where IL-1 levels are elevated endogeneously (rather than by exogenous administration), the mechanism by which IL-1 activates the HPA axis is determined largely by the anatomic location of the tissues and bodily fluids that possess markedly increased IL-1 concentrations. In this respect, distinct proposed mechanisms seem most appropriate to the situations where IL-1 is increased in blood, peripheral tissue, or the brain. In reality, however, the extent to which elevations in cytokine concentrations can be compartmentalized on an anatomic basis is unclear. For example, it might be assumed that during a local inflammatory insult when IL-1 levels are elevated only at the local site of tissue damage, a neural afferent mechanism seems the most likely candidate pathway for activation of the HPA axis. However, because IL1 induces the secretion of IL-6, which subsequently gains access to the systemic circulation, it seems likely that IL6 is, at least partly, responsible for activation of the HPA axis. An additional complication is that none of the proposed mechanisms of activation of the HPA axis by cytokines takes into account the fact that elaboration of a single cytokine in response to a homeostatic threat is an unlikely event. Furthermore, there are no systematic studies of the mechanisms by which multiple cytokines (e.g., IL-1 plus IL-6) may induce HPA axis activation. Perhaps the most striking feature of the numerous studies investigating the mechanisms of IL-1 induced activation of the HPA axis is the tremendous diversity of plausible immune-neuroendocrine interactions. This diversity ensures that the occurrence of challenges to cellular, tissue, or system homeostasis is reliably conveyed to the neuroendocrine hypothalamus. Volume 79 January 1999 20. 21. 22. 23. 24. 25. 26. 27. 29. 30. 31. 32. 33. 34. 35. 36. 37. 38. 39. thalamic magnocellular neurosecretory nuclei of the rat. Brain Res. Bull. 28: 599–603, 1992. ARZT, E., R. BURIC, G. STELZER, J. STALLA, J. SAUER, U. RENNER, AND G. K. STALLA. Interleukin involvement in anterior pituitary cell growth regulation: effects of IL-2 and IL-6. Endocrinology 132: 459–467, 1993. ARZT, E., AND G. K. STALLA. Cytokines: autocrine and paracrine roles in the anterior pituitary. Neuroimmunomodulation 3: 28– 34, 1996. ARZT, E., G. STEIZER, U. RENNER, M. LANGE, O. A. MULLER, AND G. K. STALLA. Interleukin-2 and interleukin-2 receptor expression in human corticotrophic adenoma and murine pituitary cell cultures. J. Clin. Invest. 90: 1944–1951, 1992. ATKINS, E. Pathogenesis of fever. Physiol. Rev. 40: 580–646, 1960. ATKINS, M. B., J. A. GOULD, M. ALLEGRETTA, J. J. LI, R. A. DEMPSEY, R. A. RUDDERS, D. R. PARKINSON, S. REICHLIN, AND J. W. MIER. Phase I evaluation of recombinant interleukin-2 in patients with advanced malignant disease. J. Clin. Oncol. 4: 1380–1391, 1986. AUBRY, J.-M., A. V. TURNBULL, G. P. POZZOLI, C. RIVIER, AND W. VALE. Endotoxin and interleukin-1b decrease corticotropinreleasing factor receptor type I mRNA levels in the rat pituitary. Endocrinology 138: 1621–1626, 1997. BAES, M., W. ALLAERTS, AND C. DENEF. Evidence for functional communication between folliculo-stellate cells and hormone-secreting cells in perifused anterior pituitary cell aggregates. Endocrinology 120: 685–691, 1987. BALLMER, P. E., M. A. MCNURLAN, B. G. SOUTHORN, I. GRANT, AND P. J. GARLICK. Effects of human interleukin-1 beta on protein synthesis in rat tissues compared with a classical acute-phase response reaction induced by turpentine. Rapid response of muscle to interleukin-1 beta. Biochem. J. 279: 683–688, 1991. BAN, E. M., F. HAOUR, AND R. LENSTRA. Brain interleukin-1 gene expression induced by peripheral lipopolysaccharide administration. Cytokine 4: 48–54, 1992. BAN, E., C. MARQUETTE, A. SARRIEAU, F. FITZPATRICK, G. FILLION, G. MILON, W. ROSTENE, AND F. HAOUR. Regulation of interleukin-1 receptor expression in mouse brain and pituitary by lipopolysaccharide and glucocorticoids. Neuroendocrinology 58: 581–587, 1993. BAN, E. M., G. MILON, N. PRUDHOMME, G. FILLION, AND F. HAOUR. Receptors for interleukin-1 (a and b) in mouse brain: mapping and neuronal localization in hippocampus. Neuroscience 43: 21–30, 1991. BAN, E., L. SARLIEVE, AND F. HAOUR. Interleukin-1 binding sites on astrocytes. Neuroscience 52: 725–733, 1993. BANDTLOW, C. E., M. MEYER, D. LINDHOLM, M. SPRANGER, R. HEUMANN, AND H. THOENEN. Regional and cellular codistribution of interleukin 1b and nerve growth factor mRNA in the adult rat brain: possible relationship to the regulation of nerve growth factor synthesis. J. Cell Biol. 111: 1701–1711, 1990. BANKS, W. A., AND A. J. KASTIN. The interleukin-1a, -1b, and -2 do not acutely disrupt the murine blood-brain barrier. Int. J. Immunopharmacol. 14: 629–636, 1992. BANKS, W. A., A. J. KASTIN, AND R. D. BROADWELL. Passage of cytokines across the blood-brain barrier. Neuroimmunomodulation 2: 241–248, 1995. BANKS, W. A., A. J. KASTIN, AND D. A. DURHAM. Bidirectional transport of interleukin-1 alpha across the blood-brain-barrier. Brain Res. Bull. 23: 433–437, 1989. BANKS, W. A., A. J. KASTIN, AND E. G. GUTIERREZ. Penetration of interleukin-6 across the murine blood-brain-barrier. Neurosci. Lett. 179: 53–56, 1994. BANKS, W. A., L. ORTIZ, S. R. PLOTKIN, AND A. J. KASTIN. Human interleukin (IL) 1a, murine IL-1a and murine IL-1b are transported from blood to brain in the mouse by a shared saturable transport mechanism. J. Pharmacol. Exp. Ther. 259: 988–996, 1991. BARBACID, M. The Trk family of neurotrophin receptors. J. Neurobiol. 25: 1386–1403, 1994. BARBANEL, G., S. GAILLET, M. MEKAOUCHE, L. GIVALOIS, G. IXART, P. SIAUD, A. SZAFARCZYK, F. MALAVAL, AND I. ASSENMACHER. Complex catecholaminergic modulation of the stimula- / 9j0c$$oc11 P13-8 40. 41. 42. 43. 44. 45. 46. 47. 48. 49. 50. 51. 52. 53. 54. 55. 56. 11-25-98 11:16:36 45 tory effect of interleukin-1b on the corticotropic axis. Brain Res. 626: 31–36, 1993. BARBANEL, G., G. IXART, A. SZAFARCZYK, F. MALAVAL, AND I. ASSENMACHER. Intrahypothalamic infusion of interleukin-1b increases the release of corticotropin-releasing hormone (CRH 41) and adrenocorticotropic hormone (ACTH) in free-moving rats bearing a push-pull cannula in the median eminence. Brain Res. 516: 31–36, 1990. BARBARINO, A., S. COLASANTI, S. M. CORSELLO, M. A. SATTA, S. D. CASA, C. A. ROTA, R. TARTAGLIONE, AND A. BAINI. Dexamethasone inhibition of interferon-g2-induced stimulation of cortisol and growth hormone secretion in chronic myeloproliferative syndrome. J. Clin. Endocrinol. Metab. 80: 1329–1332, 1995. BARTFAI, T., C. ANDERSSON, J. BRISTULF, M. SCHULTZBERG, AND S. SVENSON. Interleukin-1 in the noradrenergic chromaffin cells in the rat adrenal medulla. Ann. NY Acad. Sci. 207–213, 1990. BARTLETT, W. P., X. S. LI, M. WILLIAMS, AND S. BENKOVIC. Localization of insulin-like growth factor-1 mRNA in murine central nervous system during postnatal development. Dev. Biol. 147: 239–250, 1991. BASILE, D. P., AND M. A. HOLZWARTH. Basic fibroblast growth factor may mediate proliferation in the compensatory adrenal growth response. Am. J. Physiol. 265 (Regulatory Integrative Comp. Physiol. 34): R1253–R1261, 1993. BATSHAKE, B., C. NILSSON, AND J. SUNDELIN. Molecular characterization of the mouse prostanoid EP1 receptor gene. Eur. J. Biochem. 231: 809–814, 1995. BAZAN, J. F., J. C. TIMANS, AND R. A. KASTELEIN. A newly identified interleukin-1? Nature 379: 591, 1996. BAZZONI, F., AND B. BEUTLER. The tumor necrosis factor ligand and receptor families. N. Engl. J. Med. 334: 1717–1725, 1996. BEACH, J. E., R. C. SMALLRIDGE, C. A. KINZER, E. W. BERNTON, J. W. HOLADAY, AND H. G. FEIN. Rapid release of multiple hormones from rat anterior pituitaries perifused with recombinant interleukin-1. Life Sci. 44: 1–7, 1989. BEBO, B. F., AND D. S. LINTHICUM. Expression of mRNA for 55kDa and 75-kDa tumor necrosis factor (TNF) receptors in mouse cerebrovascular endothelium: effects of interleukin-1 beta, interferon-gamma and TNF-alpha on cultured cells. J. Neuroimmunol. 62: 161–167, 1995. BEN HUR, T., J. ROSENTHAL, A. ITZIK, AND J. WEIDENFELD. Adrenocortical activation by herpes virus: involvement of IL-1 beta and central noradrenergic system. Neuroreport 7: 927–931, 1996. BENIGNI, F., R. FAGGIONI, M. SIRONI, G. FANTUZZI, P. VANDENABEELE, N. TAKAHASHI, S. SACCO, W. FIERS, W. A. BUURMAN, AND P. GHEZZI. TNF receptor p55 plays a major role in centrally mediated increases of serum IL-6 and corticosterone after intracerebroventricular injection of TNF. J. Immunol. 157: 5563–5568, 1996. BENIGNI, F., G. FANTUZZI, S. SACCO, M. SIRONI, P. POZZI, C. A. DINARELLO, J. D. SIPE, V. POLI, M. CAPPELLETTI, G. PAONESSA, D. PENNICA, N. PANAYOTATOS, AND P. GHEZZI. Six different cytokines that share gp130 as a receptor subunit, induce serum amyloid A and potentiate the induction of interleukin-6 and the activation of the hypothalamo-pituitary-adrenal axis by interleukin-1. Blood 87: 1851–1854, 1996. BERGERS, G., A. REIKERSTORFER, S. BRASELMANN, P. GRANINGER, AND M. BUSSLINGER. Alternative promoter usage of the Fos-responsive gene Fit-1 generates mRNA isoforms coding for either secreted or membrane-bound proteins related to the IL-1 receptor. EMBO J. 13: 1176–1188, 1994. BERKENBOSCH, F., D. E. C. DEGOEIJ, A. DEL REY, AND H. O. BESEDOVSKY. Neuroendocrine, sympathetic and metabolic responses induced by interleukin-1. Neuroendocrinology 50: 570– 576, 1989. BERKENBOSCH, F., J. VAN OERS, A. DEL REY, F. TILDERS, AND H. BESEDOVSKY. Corticotropin-releasing factor-producing neurons in the rat activated by interleukin-1. Science 238: 524– 526, 1987. BERNARDINI, R., A. E. CALOGERO, G. MAUCERI, AND G. P. CHROUSOS. Rat hypothalamic corticotropin-releasing hormone pra APS-Phys Rev Downloaded from on April 23, 2014 28. REGULATION OF HPA AXIS BY CYTOKINES 46 57. 58. 59. 60. 61. 62. 63. 65. 66. 67. 68. 69. 70. 71. 72. 73. 74. 75. 76. secretion in vitro is stimulated by interleukin-1 in an eicosanoid dependent manner. Life Sci. 47: 1601–1607, 1990. BERNARDINI, R., A. CHIARENZA, A. E. CALOGERO, P. W. GOLD, AND G. P. CHROUSOS. Arachidonic acid metabolites modulate rat hypothalamic corticotropin-releasing hormone secretion in vitro. Neuroendocrinology 50: 708–715, 1989. BERNARDINI, R., T. C. KAMILARIS, A. E. CALOGERO, E. O. JOHNSON, M. T. GOMEZ, P. W. GOLD, AND G. P. CHROUSOS. Interactions between tumor necrosis factor-a, hypothalamic corticotropin-releasing hormone, and adrenocorticotropin secretion in the rat. Endocrinology 126: 2876–2881, 1990. BERNARDINI, R., G. MAUCERI, M. P. IURATO, A. CHIARENZA, L. LEMPEREUR, AND U. SCAPAGNINI. Response of the hypothalamic-pituitary-adrenal axis to interleukin 1 in the aging rat. Prog. Neuroendocrinol. Immunol. 5: 166–171, 1992. BERNHAGEN, J., T. CALANDRA, R. A. MITCHELL, S. B. MARTIN, K. J. TRACEY, W. VOELTER, K. R. MANOGUE, A. CERAMI, AND R. BUCALA. Macrohpage migration inhibitory factor (MIF) is a pituitary-derived cytokine that potentiates lethal endotoxemia. Nature 365: 756–759, 1993. BERNHAGEN, J., R. A. MITCHELL, T. CALANDRA, W. VOELTER, A. CERAMI, AND R. BUCALA. Purification, bioactivity and secondary structure analysis of mouse and human macrophage migration inhibitory factor (MIF). Biochemistry 33: 14144–14155, 1994. BERNTON, E. W., J. E. BEACH, J. W. HOLADAY, R. C. SMALLRIDGE, AND H. G. FEIN. Release of multiple hormones by a direct action of interleukin-1 on pituitary cells. Science 238: 519– 521, 1987. BESEDOVSKY, H., AND A. DEL REY. Neuroendocrine and metabolic responses induced by interleukin-1. J. Neurosci. Res. 18: 172–178, 1987. BESEDOVSKY, H. O., AND A. DEL REY. Mechanism of virus-induced stimulation of the hypothalamus-pituitary-adrenal axis. J. Steroid Biochem. Mol. Biol. 34: 235–239, 1989. BESEDOVSKY, H. O., AND A. DEL REY. Immune-neuroendocrine interactions: facts and hypotheses. Endocr. Rev. 17: 64–102, 1996. BESEDOVSKY, H. O., A. DEL REY, I. KLUSMAN, H. FURUKAWA, G. M. ARDITI, AND A. KABIERSCH. Cytokines as modulators of the hypothalamus-pituitary-adrenal axis. J. Steroid Biochem. Mol. Biol. 40: 613–618, 1991. BESEDOVSKY, H. O., A. DEL REY, AND E. SORKIN. Antigenic competition between horse and sheep red blood cells as hormonedependent phenomenon. Clin. Exp. Immunol. 37: 106–113, 1979. BESEDOVSKY, H. O., A. DEL REY, AND E. SORKIN. Lymphokinecontaining supernatants from Con A-stimulated cells increase corticosterone blood levels. J. Immunol. 126: 385–387, 1981. BESEDOVSKY, H., A. DEL REY, E. SORKIN, M. DA PRADA, R. BURRI, AND C. G. HONEGGER. The immune response evokes changes in brain noradrenergic neurons. Science 221: 564–566, 1983. BESEDOVSKY, H., A. DEL REY, E. SORKIN, AND C. A. DINARELLO. Immunoregulatory feedback between interleukin-1 and glucocorticoid hormones. Science 233: 652–654, 1986. BESEDOVSKY, H. O., A. DEL REY, E. SORKIN, W. LOTZ, AND U. SCHWULERA. Lymphoid cells produce an immunoregulatory glucocorticoid increasing factor (GIF) acting through the pituitary gland. Clin. Exp. Immunol. 59: 622–628, 1985. BESEDOVSKY, H., E. SORKIN, D. FELIX, AND H. HAAS. Hypothalamic changes during the immune response. Eur. J. Immunol. 7: 323–325, 1977. BESEDOVSKY, H., E. SORKIN, M. KELLER, AND J. MULLER. Changes in blood hormone levels during the immune response. Proc. Soc. Exp. Biol. Med. 150: 466–470, 1975. BILEZIKJIAN, L. M., A. L. BLOUNT, C. A. CAMPEN, C. GONZALEZ-MANCHON, AND W. VALE. Activin-A inhibits proopiomelanocortin messenger RNA accumulation and adrenocorticotropin secretion of AtT20 cells. Mol. Endocrinol. 5: 1389–1395, 1991. BILEZIKJIAN, L. M., A. Z. CORRIGAN, AND W. W. VALE. ActivinB, inhibin-B and follistatin as autocrine/paracrine factors of the rat anterior pituitary. Front. Neuroendocrinol. 3: 1–19, 1994. BINDONI, M., V. PERCIAVALLE, S. BERRETTA, N. BELLUARDO, AND T. DIAMANTSTEIN. Interleukin 2 modifies the bioelectric / 9j0c$$oc11 P13-8 77. 78. 79. 80. 81. 82. 83. 84. 85. 86. 87. 88. 89. 90. 91. 92. 93. 94. 95. 96. 97. 98. 11-25-98 11:16:36 Volume 79 activity of some neurosecretory nuclei in the rat hypothalamus. Brain Res. 462: 10–14, 1988. BISHAI, I., AND F. COCEANI. Differential effects of endotoxin and cytokines on prostaglandin E2 formation in cerebral microvessels and brain parenchyma: implications for the pathogenesis of fever. Cytokine 8: 371–376, 1996. BISHAI, I., C. DINARELLO, AND F. COCEANI. Prostaglandin formation in feline cerebral microvessels: effects of endotoxin and interleukin-1. Can. J. Physiol. Pharmacol. 65: 2225–2230, 1987. BLALOCK, J. E. Proopiomelanocortin-derived peptides in the immune system. Clin. Endocrinol. 22: 823–827, 1985. BLALOCK, J. E. A molecular basis for bidirectional communication between the immune and neuroendocrine systems. Physiol. Rev. 69: 1–32, 1989. BLALOCK, J. E. The syntax of immune-neuroendocrine communication. Immunol. Today 15: 504–511, 1994. BLALOCK, J. E., D. HARBUR-MCMENAMIN, AND E. M. SMITH. Peptide hormones shared by the neuroendocrine and immunologic systems. J. Immunol. 135, Suppl.: 858s–861s, 1985. BLALOCK, J. E., H. M. JOHNSON, E. M. SMITH, AND B. A. TORRES. Enhancement of the in vitro antibody response by thyrotropin. Biochem. Biophys. Res. Commun. 125: 30–34, 1984. BLALOCK, J. E., AND J. D. STANTON. Common pathways of interferon and hormonal action. Nature 283: 406–408, 1980. BLATTEIS, C. M. Neuromodulative actions of cytokines. Yale J. Biol. Med. 63: 133–146, 1990. BLATTEIS, C. M. The OVLT: the interface between the brain and circulating pyrogens. In: Neuroimmunology of Fever, edited by T. Bartfai and D. Ottoson. Oxford, UK: Pergamon, 1992, p. 167– 176. BLUETHMANN, H., J. ROTHE, N. SCHULTZE, M. TKACHUK, AND P. KOEBEL. Establishment of the role of IL-6 and TNF receptor 1 using gene knockout mice. J. Leukoc. Biol. 56: 565–570, 1994. BLUTHE, R.-M., B. MICHAUD, K. W. KELLEY, AND R. DANTZER. Vagotomy attenuates behavioral effects of interleukin-1 injected peripherally but not centrally. Neuroreport 7: 1485–1488, 1996. BLUTHE, R. M., B. MICHAUD, K. W. KELLEY, AND R. DANTZER. Vagotomy blocks behavioural effects of interleukin-1 injected via the intraperitoneal route but not via other systemic routes. Neuroreport 7: 2823–2827, 1996. BLUTHE, R. M., V. WALTER, P. PARNET, S. LAYE, J. LESTAGE, D. VERRIER, S. POOLE, B. E. STENNING, K. W. KELLEY, AND R. DANTZER. Lipopolysaccharide induces sickness behavior in rats by a vagal mediated mechanism. C. R. Acad. Sci. III 317: 499– 503, 1994. BOJE, K. M. Cerebrovascular permeability changes during experimental meningitis in the rat. J. Pharmacol. Exp. Ther. 274: 1199– 1203, 1995. BOKA, G., P. ANGLADE, D. WALLACH, F. JAVOY-AGID, Y. AGID, AND E. C. HIRSCH. Immunocytochemical analysis of tumor necrosis factor and its receptors in Parkinson’s disease. Neurosci. Lett. 172: 151–154, 1995. BONDY, C., H. WERNER, C. T. ROBERTS, AND D. LEROITH. Cellular pattern of type-I insulin-like growth factor receptor gene expression during maturation of the rat brain: comparison with insulin-like growth factors I and II. Neuroscience 46: 909–923, 1992. BONNERT, T. P., K. E. GARKA, P. PARNET, G. SONODA, J. R. TESTA, AND J. E. SIMS. The cloning and characterization of human MyD88: a member of an IL-1 receptor related family. FEBS Lett. 402: 81–84, 1997. BOUSQUET, C., D. W. RAY, AND S. MELMED. A common proopiomelanocortin-binding element mediates leukemia inhibitory factor and corticotropin-releasing hormone transcriptional synergy. J. Biol. Chem. 272: 10551–10557, 1997. BOYLE, M., G. YAMAMOTO, M. CHEN, J. RIVIER, AND W. VALE. Interleukin 1 prevents loss of corticotropic responsiveness to beta-adrenergic stimulation in vitro. Proc. Natl. Acad. Sci. USA 85: 5556–5560, 1988. BRACH, M. A., B. LOWENBERG, L. MONTOVANI, U. SCHWULERA, R. MERTELSMANN, AND F. HERRMAN. Interleukin-6 (IL-6) is an intermediate in IL-1-induced proliferation of leukemic human megakaryocytes. Blood 76: 1972–1979, 1990. BRADY, L. S., A. B. LYNN, M. HERKENHAM, AND Z. GOTTES- pra APS-Phys Rev Downloaded from on April 23, 2014 64. ANDREW V. TURNBULL AND CATHERINE L. RIVIER January 1999 99. 100. 101. 102. 103. 104. 105. 106. 108. 109. 110. 111. 112. 113. 114. 115. 116. 117. FELD. Systemic interleukin-1 induces early and late patterns of c-fos mRNA expression in brain. J. Neurosci. 14: 4951–4964, 1994. BRANDT, E. R., I. R. MACKAY, P. J. HERTZOG, B. F. CHEETHAM, M. SHERRITT, AND C. C. BERNARD. Molecular detection of interferon-alpha expression in multiple sclerosis brain. J. Neuroimmunol. 44: 1–5, 1993. BREDER, C. D., D. DEWITT, AND R. P. KRAIG. Characterization of inducible cyclooxygenase in rat brain. J. Comp. Neurol. 355: 296–315, 1995. BREDER, C. D., C. A. DINARELLO, AND C. B. SAPER. Interleukin1 immunoreactive innervation of the human hypothalamus. Science 240: 321–323, 1988. BREDER, C. D., C. HAZUKA, T. GHAYUR, C. KLUG, M. HUGININ, K. YASUDA, M. TENG, AND C. B. SAPER. Regional distribution of tumor necrosis factor a expression in the mouse brain after systemic lipopolysaccharide administration. Proc. Natl. Acad. Sci. USA 91: 11393–11397, 1994. BREDER, C. D., AND C. B. SAPER. Expression of inducible cyclooxygenase mRNA in the mouse brain after systemic administration of bacterial lipopolysaccharide. Brain Res. 713: 64–69, 1996. BREDER, C. D., W. L. SMITH, A. RAZ, J. MASFERRER, K. SEIBERT, P. NEEDLEMAN, AND C. B. SAPER. Distribution and characterization of cyclooxygenase immunoreactivity in the ovine brain. J. Comp. Neurol. 322: 409–438, 1992. BREDER, C. D., M. TSUJIMOTO, Y. TERANO, D. W. SCOTT, AND C. B. SAPER. Distribution and characterization of tumor necrosis factor-a-like immunoreactivity in the murine central nervous system. J. Comp. Neurol. 337: 543–567, 1993. BREDT, D. S., G. E. GLATT, P. M. HWANG, M. FOTUHI, T. M. DAWSON, AND S. H. SNYDER. Nitric oxide synthase protein and mRNA are discretely localized in neuronal populations of the mammalian CNS together with NADPH diaphorase. Neuron 7: 615–624, 1991. BREDT, D. S., P. M. HWANG, AND S. H. SNYDER. Localization of nitric oxide synthase indicating a neural role for nitric oxide. Nature 347: 768–770, 1990. BRET-DIBAT, J.-L., R.-M. BLUTHE, S. KENT, K. W. KELLEY, AND R. DANTZER. Lipopolysaccharide and interleukin-1 depress foodmotivated behavior in mice by a vagal-mediated mechanism. Brain Behav. Immun. 9: 242–246, 1995. BRET-DIBAT, J. L., C. CREMINON, J. Y. COURAUD, K. W. KELLEY, R. DANTZER, AND S. KENT. Systemic capsaicin pretreatment fails to block the decrease in food-motivated behavior induced by lipopolysaccharide and interleukin-1 beta. Brain Res. Bull. 42: 443–449, 1997. BRISTULF, J., AND T. BARTFAI. Interleukin-1b and tumor necrosis factor-a stimulate the mRNA expression of interleukin-1 receptors in mouse anterior pituitary AtT-20 cells. Neurosci. Lett. 187: 53– 56, 1995. BRISTULF, J., A. SIMONCSITS, AND T. BARTFAI. Characterization of a neuronal interleukin-1 receptor and the corresponding mRNA in the mouse anterior pituitary cell line AtT-20. Neurosci. Lett. 128: 173–176, 1991. BRODISH, A. Extra-CNS corticotropin-releasing factors. Ann. NY Acad. Sci. 297: 420–435, 1977. BRODISH, A. Tissue corticotropin releasing factors. Federation Proc. 36: 2088–2093, 1977. BROSH, N., D. STERNBERG, J. HONIGWACHS-SHA’ANANI, B.C. LEE, Y. SHAV-TAL, E. TZEHOVAL, L. M. SHULMAN, J. TOLEDO, Y. HACHMAN, P. CARMI, W. JIANG, J. SASSE, F. HORN, Y. BURSTEIN, AND D. ZIPORI. The plasmacytoma growth inhibitor restrictin-P is an antagonist of interleukin-6 and interleukin-11. J. Biol. Chem. 270: 29594–29600, 1995. BROWN, S. L., L. R. SMITH, AND J. E. BLALOCK. Interleukin-1 and interleukin-2 enhance proopiomelanocortin gene expression in pituitary cells. J. Immunol. 139: 3181–3183, 1987. BRUNETTI, L., P. PREZIOSI, E. RAGAZZONI, AND M. VACCA. Involvement of nitric oxide in basal and interleukin-1 beta-induced CRF and ACTH release in vitro. Life Sci. 53: 219–222, 1993. BRUNETTI, L., P. PREZIOSI, E. RAGAZZONI, AND M. VACCA. Effects of lipopolysaccharide on hypothalamic-pituitary-adrenal axis in vitro. Life Sci. 54: 165–171, 1994. / 9j0c$$oc11 P13-8 47 118. BUCALA, R. Identification of MIF as a new pituitary hormone and macrophage cytokine and its role in endotoxic shock. Immunol. Lett. 43: 23–26, 1994. 119. BUCALA, R. MIF, a previously unrecognized pituitary hormone and macrophage cytokine, is a pivotal mediator in endotoxic shock. Circ. Shock 44: 35–39, 1994. 120. BUCALA, R. MIF rediscovered: cytokine, pituitary hormone, and glucocorticoid-induced regulator of the immune response. FASEB J. 10: 1607–1613, 1996. 121. BUCKINGHAM, J. C., H. D. LOXLEY, H. C. CHRISTIAN, AND J. G. PHILIP. Activation of the HPA axis by immune insults: roles and interactions of cytokines, eicosanoids, and glucocorticoids. Pharmacol. Biochem. Behav. 54: 285–298, 1996. 122. BURGER, D., AND J.-M. DAYER. Inhibitory cytokines and cytokine inhibitors. Neurology 45, Suppl.: S39–S43, 1995. 123. BURRELL, R. Human responses to bacterial endotoxin. Circ. Shock 43: 137–153, 1994. 124. BUTTINI, M., AND H. BODDEKE. Peripheral lipopolysaccharide stimulation induces interleukin-1b messenger RNA in rat brain microglial cells. Neuroscience 65: 523–530, 1995. 125. CAHAO, M. V. Neurotrophin receptors: a window into neuronal differentiation. Neuron 9: 583–593, 1992. 126. CALANDRA, T., J. BERHAGEN, C. N. METZ, L. A. SPIEGEL, M. BACHER, T. DONNELLY, A. CERAMI, AND R. BUCALA. MIF as a glucocorticoid-induced modulator of cytokine production. Nature 377: 68–71, 1995. 127. CALKA, J., AND C. H. BLOCK. Relationship of vasopressin with NADPH-diaphorase in the hypothalamo-neurohypophysial system. Brain Res. Bull. 32: 207–210, 1993. 128. CALLAHAN, T. A., AND D. T. PIEKUT. Differential Fos expression induced by IL-1 beta and IL-6 in rat hypothalamus and pituitary gland. J. Neuroimmunol. 73: 207–211, 1997. 129. CALZA, L., L. GIARDINO, AND S. CECCATELLI. NOS mRNA in the paraventricular nucleus of young and aged rats after immobilization stress. Neuroreport 4: 627–630, 1993. 130. CAMBRONERO, J. C., J. BORRELL, AND C. GUAZA. Glucocorticoids modulate rat hypothalamic corticotropin-releasing factor release induced by interleukin-1. J. Neurosci. Res. 24: 470–476, 1989. 131. CAMBRONERO, J. C., F. J. RIVAS, J. BORREL, AND C. GUAZA. Interleukin-2 induces corticotropin-releasing hormone release from superfused rat hypothalami: influence of glucocorticoids. Endocrinology 131: 677–683, 1992. 132. CAMBRONERO, J. C., F. J. RIVAS, J. BORREL, AND C. GUAZZA. Interleukin-1-beta induces pituitary adrenocorticotropin secretion: evidence for glucocorticoid modulation. Neuroendocrinology 55: 648–654, 1992. 133. CAMBRONERO, J. C., F. J. RIVAS, J. BORRELL, AND C. GUAZA. Adrenalectomy does not change CRF secretion induced by interleukin-1 from rat perifused hypothalami. Regul. Peptides 41: 237–247, 1992. 134. CAMBRONERO, J. C., F. J. RIVAS, J. BORRELL, AND C. GUAZA. Release of corticotropin-releasing factor from superfused hypothalami induced by interleukin-1 is not dependent on adrenergic mechanism. Eur. J. Pharmacol. 219: 75–80, 1992. 135. CAMBRONERO, J. C., J. RIVAS, J. BORRELL, AND C. GUAZA. Role of arachidonic acid metabolism on corticotropin-releasing factor (CRF)-release induced by interleukin-1 from superfused rat hypothalami. J. Neuroimmunol. 39: 57–66, 1992. 136. CAMERON, V. A., E. NISHIMURA, L. S. MATHEWS, K. A. LEWIS, P. E. SAWCHENKO, AND W. W. VALE. Hybridization histochemical localization of activin preceptor subtypes in rat brain, pituitary, ovary, and testis. Endocrinology 134: 799–808, 1994. 137. CANNON, J. G., AND C. A. DINARELLO. Increased plasma interleukin-1 activity in women after ovulation. Science 227: 1247–1249, 1985. 138. CANNON, J. G., R. A. FIELDING, M. A. FIATARONE, S. F. ORENCOLE, C. A. DINARELLO, AND W. J. EVANS. Increased interleukin-1 beta in human skeletal muscle after exercise. Am. J. Physiol. 257 (Regulatory Integrative Comp. Physiol. 26): R451–R455, 1989. 139. CANNON, J. G., AND M. J. KLUGER. Endogenous pyrogen activity in human plasma after exercise. Science 220: 617–619, 1983. 140. CAO, C., K. MATSUMURA, K. YAMAGATA, AND Y. WATANABE. 11-25-98 11:16:36 pra APS-Phys Rev Downloaded from on April 23, 2014 107. REGULATION OF HPA AXIS BY CYTOKINES 48 141. 142. 143. 144. 145. 146. 147. 149. 150. 151. 152. 153. 154. 155. 156. 157. 158. Induction by lipopolysaccharide of cyclooxygenase-2 mRNA in rat brain: its possible role in the febrile response. Brain Res. 697: 187–196, 1995. CAO, C., K. MATSUMURA, K. YAMAGATA, AND Y. WATANABE. Endothelial cells of the rat brain vasculature express cyclooxygenase-2 mRNA in response to systemic interleukin-1 beta: a possible site of prostaglandin synthesis responsible for fever. Brain Res. 733: 263–272, 1996. CAO, C., K. MATSUMURA, K. YAMAGATA, AND Y. WATANABE. Involvememnt of cyclooxygenase-2 in LPS-induced fever and regulation of its mRNA by LPS in the rat brain. Am. J. Physiol. 272 (Regulatory Integrative Comp. Physiol. 41): R1712–R1725, 1997. CARDOSO, E., E. ARZT, M. COUMROGLON, E. C. ANDRADA, AND J. A. ANDRADA. Alpha-interferon induces cortisol release by human adrenals in vitro. Int. Arch. Allergy Appl. Immunol. 93: 263–266, 1990. CARLSON, D. E. Adrenocorticotropin correlates strongly with endotoxemia after intravenous but not after intraperitoneal inoculations of E. coli. Shock 7: 65–69, 1997. CARMELIET, P., H. VANKELECOM, J. VAN DAMME, A. BILLIAU, AND C. DENEF. Release of interleukin-6 from anterior pituitary cell aggregates: developmental pattern and modulation by glucocorticoids and forskolin. Neuroendocrinology 53: 29–34, 1991. CASTELL, J. V., T. GEIGER, V. GROSS, T. ANDUS, E. WALTER, T. HIRANO, T. KISHIMOTO, AND P. C. HEINRICH. Plasma clearance, organ distribution and target cells of interleukin-6/hepatocytestimulating factor in the rat. Eur. J. Biochem. 177: 357–361, 1988. CECCATELLI, S., AND M. ERIKSSON. The effect of lactation on nitric oxide synthase gene expression. Brain Res. 625: 177–179, 1993. CECCATELLI, S., A. L. HULTING, X. ZHANG, L. GUSTAFSSON, M. VILLAR, AND T. HOKFELT. Nitric oxide synthase in the rat anterior pituitary gland and the role of nitric oxide in regulation of luteinizing hormone secretion. Proc. Natl. Acad. Sci. USA 90: 11292–11296, 1993. CECCATELLI, S., J. M. LUNDBERG, J. FAHRENKRUG, D. S. BREDT, S. H. SNYDER, AND T. HOEKFELT. Evidence for the involvement of nitric oxide in the regulation of hypothalamic portal blood flow. Neuroscience 51: 769–772, 1992. CHAI, Z., S. GATTI, C. TONIATTI, V. POLI, AND T. BARTFAI. Interleukin (IL)-6 gene expression in the central nervous system is necessary for fever response to lipopolysaccharide of IL-1b: a study on IL-6 deficient mice. J. Exp. Med. 183: 311–316, 1996. CHAIDARUN, S. S., M. C. EGGO, P. M. STEWART, AND M. C. SHEPPARD. Modulation of epidermal growth factor binding and receptor gene expression by hormones and growth factors in sheep pituitary cells. J. Endocrinol. 143: 489–496, 1994. CHAN, R. K. W., E. R. BROWN, A. ERICSSON, K. J. KOVACS, AND P. E. SAWCHENKO. A comparison of two immediate-early genes, c-fos and NGFI-B, as markers for functional activation in stressrelated neuroendocrine circuitry. J. Neurosci. 13: 5126–5138, 1993. CHANG, S. L., T. REN, AND J. E. ZADINA. Interleukin-1 activation of FOS proto-oncogene protein in the rat hypothalamus. Brain Res. 617: 123–130, 1993. CHANG, Y., S. ALBRIGHT, AND F. LEE. Cytokines in the central nervous system: expression of macrophage colony stimulating factor and its receptor during development. J. Neuroimmunol. 52: 9–17, 1994. CHEIFETZ, S., N. LING, R. GUILLEMAN, AND J. MASSAGUE. A surface component on GH3 pituitary cells that recognizes transforming growth factor-b, activin and inhibin. J. Biol. Chem. 263: 17225–17228, 1988. CHILDS, G. V., J. PATTERSON, G. UNABIA, D. ROUGEAU, AND P. WU. Epidermal growth factor enhances ACTH secretion and expression of POMC mRNA by corticotropes in mixed and enriched cultures. Mol. Cell. Neurosci. 2: 235–243, 1991. CHILDS, G. V., D. ROUGEAU, AND G. UNABIA. Corticotropin-releasing hormone and epidermal growth factor: mitogens for anterior pituitary corticotropes. Endocrinology 136: 1595–1602, 1995. CHOVER-GONZALEZ, A. J., S. L. LIGHTMAN, AND M. S. HARBUZ. An investigation of the effects of interleukin-1b on plasma arginine / 9j0c$$oc11 P13-8 159. 160. 161. 162. 163. 164. 165. 166. 167. 168. 169. 170. 171. 172. 173. 174. 175. 176. 177. 11-25-98 11:16:36 Volume 79 vasopressin in the rat: role of adrenal steroids. J. Endocrinol. 142: 361–366, 1994. CHRISTENSEN, J. D., E. W. HANSEN, AND B. FJALLAND. Influence of interleukin-1b on the secretion of oxytocin and vasopressin from the isolated rat neurohypophysis. Pharmacol. Toxicol. 67: 81–83, 1990. CHULUYAN, H. E., D. SAPHIER, W. M. ROHN, AND A. J. DUNN. Noradrenergic innervation of the hypothalamus participates in adrenocortical responses to interleukin-1. Neuroendocrinology 56: 106–111, 1992. COCEANI, F., J. LEES, AND C. A. DINARELLO. Occurrence of interleukin-1 in cerebrospinal fluid in the conscious cat. Brain Res. 446: 245–250, 1988. COHEN, M. C., AND S. COHEN. Cytokine function. A study in biological diversity. Am. J. Clin. Pathol. 105: 589–598, 1996. COLOTTA, F., F. RE, M. MUZIO, R. BERTINI, N. POLENTARUTTI, M. SIRONI, J. G. GIRI, S. K. DOWER, J. E. SIMS, AND A. MANTOVANI. Interleukin-1 type II receptor: a decoy target for IL-1 that is regulated by IL-4. Science 261: 472–475, 1993. CONNER, J. M., AND S. VARON. Nerve growth factor immunoreactivity in the anterior pituitary of the rat. Neuroreport 4: 395–398, 1993. CONNOR, T. J., AND B. E. LEONARD. Depression, stress and immunological activation: the role of cytokines in depressive disorders. Life Sci. 62: 583–606, 1997. CONTI, B., J. W. JAHNG, C. TINTI, J. H. SON, AND T. H. JOH. Induction of interferon-gamma inducing factor in the adrenal cortex. J. Biol. Chem. 272: 2035–2037, 1997. COOPER, A. L., S. BROUWER, A. V. TURNBULL, G. N. LUHESHI, S. J. HOPKINS, S. L. KUNKEL, AND N. J. ROTHWELL. Tumor necrosis factor-alpha and fever after peripheral inflammation in the rat. Am. J. Physiol. 267 (Regulatory Integrative Comp. Physiol. 36): R1431–R1436, 1994. COOPER, A. L., AND N. J. ROTHWELL. Mechanisms of early and late hypermetabolism and fever after localized tissue injury in rats. Am. J. Physiol. 261 (Endocrinol. Metab. 24): E698–E708, 1991. COOPER, A. L., A. V. TURNBULL, S. J. HOPKINS, AND N. J. ROTHWELL. Dietary n-3 fatty acids inhibit fever induced by inflammation in the rat. Mediators Inflammation 3: 353–357, 1994. CORNFIELD, L. J., AND M. A. SILLS. High affinity interleukin-6 binding sites in bovine hypothalamus. Eur. J. Pharmacol. 202: 113–115, 1991. CORSINI, E., A. DUFOUR, E. CIUSANI, M. GELATI, S. FRIGERIO, A. GRITTI, L. CAJOLA, G. L. MANCARDI, G. MASSA, AND A. SALMAGGI. Human brain endothelial cells and astrocytes produce IL1 beta but not IL-10. Scand. J. Immunol. 44: 506–511, 1996. COSTA, A., P. TRAINER, M. BESSER, AND A. GROSSMAN. Nitric oxide modulates the release of corticotropin-releasing hormone from the rat hypothalamus in vitro. Brain Res. 605: 187–192, 1993. COULIE, P. G., M. STEVENS, AND J. VAN SNICK. High- and lowaffinity receptors for murine IL-6. Distinct distribution on B and T cells. Eur. J. Immunol. 19: 2107–2114, 1989. CREASEY, A. A., P. STEVENS, J. KENNEY, A. C. ALISON, K. WARREN, R. CATLETT, L. HINSHAW, AND F. B. TAYLOR. Endotoxin and cytokine profile in plasma of baboons challenged with lethal and sublethal Escherichia coli. Circ. Shock 33: 84–91, 1991. CROFFORD, L. J., K. T. KALOGERAS, G. MASTORAKOS, M. A. MAGIAKOU, J. WELLS, K. S. KANIK, P. W. GOLD, G. P. CHROUSOS, AND R. L. WILDER. Circadian relationship between interleukin (IL)-6 and hypothalamic-pituitary-adrenal axis hormones: failure of IL-6 to cause sustained hypercortisolism in patients with early untreated rheumatoid arthritis. J. Clin. Endocrinol. Metab. 82: 1279–1283, 1997. CROWN, J., A. JAKUBOWSKI, N. KEMENY, M. GORDON, C. GASPARETTO, G. WONG, C. SHERIDAN, G. TONER, AND J. BOTET. A phase I trial of recombinant human interleukin-1 beta alone and in combination with myelosuppressive doses of 5-fluorouracil in patients with gastrointestinal cancer. Blood 78: 1420– 1427, 1991. CUNNINGHAM, E. T., JR., E. WADA, D. B. CARTER, D. E. TRACEY, J. F. BATTEY, AND E. B. DE SOUZA. Localization of interleu- pra APS-Phys Rev Downloaded from on April 23, 2014 148. ANDREW V. TURNBULL AND CATHERINE L. RIVIER January 1999 178. 179. 180. 181. 182. 183. 184. 185. 187. 188. 189. 190. 191. 192. 193. 194. 195. 196. kin-1 receptor messenger RNA in murine hippocampus. Endocrinology 128: 2666–2668, 1991. CUNNINGHAM, E. T., JR., E. WADA, D. B. CARTER, D. E. TRACEY, J. F. BATTEY, AND E. B. DE SOUZA. In situ histochemical localization of type I interleukin-1 receptor messenger RNA in the central nervous system, pituitary, and adrenal gland of the mouse. J. Neurosci. 12: 1101–1114, 1992. CURTI, B. D., W. J. URBA, D. L. LONGO, J. E. JANIK, W. H. SHARFMAN, L. L. MILLER, G. CIZZA, M. SHIMIZU, J. J. OPPENHEIM, W. G. ALVORD, AND J. W. SMITH. Endocrine effects of IL1 alpha and beta administered in a phase I trial to patients with advanced cancer. J. Immunother. Emphasis Tumor Immunol. 19: 142–148, 1996. DARLING, G., D. S. GOLDSTEIN, R. STULL, C. M. GORTHSCHBOTH, AND J. A. NORTON. Tumor necrosis factor: immune endocrine interaction. Surgery 106: 1155–1160, 1989. DARLINGTON, D. N., J. SHINSAKO, AND M. F. DALLMAN. Medullary lesions eliminate ACTH responses to hypotensive hemorrhage. Am. J. Physiol. 251 (Regulatory Integrative Comp. Physiol. 20): R106–R115, 1986. DARNAY, B. G., AND B. B. AGGARWAL. Early events in TNF signaling: a story of associations and dissociations. J. Leukoc. Biol. 61: 559–566, 1997. DASCOMBE, M. J., AND A. S. MILTON. Study on the possible entry of bacterial endotoxin and prostaglandin E2 into the central nervous system from the blood. Br. J. Pharmacol. 66: 465–472, 1979. DAVIES, A. M. The role of neurotrophins in the developing nervous system. J. Neurobiol. 25: 1334–1348, 1994. DAVIES, A. M. Tracking neurotrophin function. Nature 368: 193– 194, 1994. DAWSON, T. M., AND S. H. SNYDER. Gases as biological messengers: nitric oxide and carbon monoxide in the brain. J. Neurosci. 14: 5147–5159, 1994. DAY, H. E. W., AND H. AKIL. Differential pattern of c-fos mRNA in rat brain following central and peripheral administration of interleukin-1-beta: implications for mechanism of action. Neuroendocrinology 63: 207–218, 1996. DE, A., T. E. MORGAN, R. C. SPETH, N. BOYADJIEVA, AND D. K. SARKAR. Pituitary lactotrope expresses transforming growth factor b (TGFb) type II receptor mRNA and protein and contains 125 I-TGFb1 binding sites. J. Endocrinol. 149: 19–27, 1996. DEFORGE, L. E., AND D. G. REMICK. Kinetics of TNF, IL-6 and IL-8 gene expression in LPS-stimulated human whole blood. Biochem. Biophys. Res. Commun. 174: 18–24, 1991. DELI, M. A., L. DESCAMPS, M. P. DEHOUCK, R. CECCHELLI, F. JOO, C. S. ABRAHAM, AND G. TORPIER. Exposure of tumor necrosis factor-alpha to luminal membrane of bovine capillary endothelial cells cocultured with astrocytes induces a delayed increase in permeability and cytoplasmic stress fiber formation. J. Neurosci. Res. 41: 717–726, 1995. DEL REY, A., H. BESEDOVSKY, AND E. SORKIN. Endogenous blood levels of corticosterone control the immunologic cell mass and B cell activity in mice. J. Immunol. 133: 572–575, 1984. DEL REY, A., H. FURUKAWA, G. MONGE-ARDITI, A. KABIERSCH, K.-H. VOIGT, AND H. O. BESEDOVSKY. Alterations in the pituitary-adrenal axis of adult mice following neonatal exposure to interleukin-1. Brain Behav. Immun. 10: 235–248, 1996. DELRUE, C., B. DELEPLANQUE, F. ROUGE-PONT, S. VITIELLO, AND P. J. NEVEU. Brain monoaminergic, neuroendocrine, and immune responses to an immune challenge in relation to brain and behavioral lateralization. Brain Behav. Immun. 8: 137–152, 1994. DENICOFF, K. D., T. M. DURKIN, M. T. LOTZE, P. E. QUINLAN, C. L. DAVIS, S. J. LISTWAK, S. A. ROSENBERG, AND D. R. RUBINOW. The neuroendocrine effects of interleukin-2 treatment. J. Clin. Endocrinol. Metab. 69: 402–410, 1989. DE RIJK, R., N. VAN ROOJEN, H. O. BESEDOVSKY, A. DEL REY, AND F. BERKENBOSCH. Selective depletion of macrophages prevents pituitary adrenal activation in response to subpyrogenic, but not pyrogenic, doses of bacterial endotoxin in rats. Endocrinology 128: 330–338, 1991. DE RIJK, R. H., A. BOELEN, F. J. H. TILDER, AND F. BERKENBOSCH. Induction of interleukin-6 by circulating adrenaline in the rat. Psychoneuroendocrinology 19: 155–163, 1994. / 9j0c$$oc11 P13-8 49 197. DE SIMONI, M. G., R. DEL BO, A. DE LUIGI, S. SIMARD, AND G. FORLONI. Central endotoxin induces different patterns of interleukin (IL)-1b and IL-6 messenger ribonucleic acid expression and IL-6 secretion in the brain and periphery. Endocrinology 136: 897–902, 1995. 198. DE SOUZA, E. B., E. L. WEBSTER, D. E. GRIGORIADIS, AND D. E. TRACEY. Corticotropin-releasing factor (CRF) and interleukin-1 receptors in the brain-pituitary-immune axis. Psychopharmacol. Bull. 25: 299–305, 1989. 199. DE VRIES, H. E., M. C. M. BLOM-POOSEMALEN, A. G. DE BOER, T. J. C. VAN BERKEL, D. D. BREIMER, AND J. K. KUIPER. Effect of endotoxin on permeability of bovine cerebral endothelial cell layers in vitro. J. Pharmacol. Exp. Ther. 277: 1418–1423, 1996. 200. DE VRIES, H. E., M. C. M. BLOM-POOSEMALEN, M. VAN OOSTEN, A. G. DE BOER, T. J. C. VAN BERKEL, D. D. BREIMER, AND J. K. KUIPER. The influence of cytokines on the integrity of the blood-brain-barrier in vitro. J. Neuroimmunol. 64: 37–43, 1996. 201. DE VRIES, H. E., K. H. HOOGENDOORN, J. VAN DIJK, F. J. ZIJLSTRA, A.-M. VAN DAM, D. D. BREIMER, T. J. C. VAN BERKEL, A. G. DE BOER, AND J. KUIPER. Eicosanoid production by rat cerebral endothelial cells: stimulation by lipopolysaccharide, interleukin-1 and interleukin-6. J. Neuroimmunol. 59: 1–8, 1995. 202. DEYERLE, K. L., J. E. SIMS, S. K. DOWER, AND M. A. BOTHWELL. Pattern of IL-1 receptor gene expression suggests role in noninflammatory processes. J. Immunol. 149: 1657–1665, 1992. 203. DINAERELLO, C. A., AND R. C. THOMPSON. Blocking IL-1: interleukin-1 receptor antagonist in vivo and in vitro. Immunol. Today 12: 404–410, 1991. 204. DINAERELLO, C. A., P. WEINER, AND S. M. WOLFF. Radiolabelling and disposition in rabbits of purified human leukocytic pyrogen (Abstract). Clin. Res. 26: 522A, 1978. 205. DINARELLO, C. A. Interleukin-1 and interleukin-1 antagonism. Blood 77: 1627–1652, 1991. 206. DINARELLO, C. A. The proinflammatory cytokines interleukin-1 and tumor necrosis factor and treatment of the septic shock syndrome. J. Infect. Dis. 163: 1177–1184, 1991. 207. DINARELLO, C. A., J. G. CANNON, J. MANCILLA, I. BISHAI, J. LEES, AND F. COCEANI. Interleukin-6 as an endogenous pyrogen: induction of prostaglandin E2 in brain but not in peripheral blood mononuclear cells. Brain Res. 562: 199–206, 1991. 208. DOBREA, G. M., J. R. UNNERSTALL, AND M. S. RAO. The expression of CNTF message and immunoreactivity in the central and peripheral nervous system of the rat. Brain Res. Dev. Brain Res. 66: 209–219, 1992. 209. DOPP, J. M., A. MACKENZIE-GRAHAM, G. C. OTERO, AND J. E. MERRILL. Differential expression, cytokine modulation, and specific functions of type-1 and type-2 tumor necrosis factor receptors in rat glia. J. Neuroimmunol. 75: 104–112, 1997. 210. DU, X., E. T. EVERETT, G. WANG, W. H. LEE, Z. YANG, AND D. A. WILLIAMS. Murine interleukin-11 (IL-11) is expressed at high levels in the hippocampus and expression is developmentally regulated in the testis. J. Cell. Physiol. 168: 362–372, 1996. 211. DUNN, A. J. Systemic interleukin-1 administration stimulates hypothalamic norepinephrine metabolism paralleling the increased plasma corticosterone. Life Sci. 43: 429–435, 1988. 212. DUNN, A. J. Endotoxin-induced activation of cerebral catecholamine and serotonin metabolism: comparison with interleukin-1. J. Pharmacol. Exp. Ther. 261: 964–969, 1992. 213. DUNN, A. J. The role of interleukin-1 and tumor necrosis factor a in the neurochemical and neuroendocrine responses to endotoxin. Brain Res. Bull. 29: 807–812, 1992. 214. DUNN, A. J. Role of cytokines in infection-induced stress. Ann. NY Acad. Sci. 697: 189–202, 1993. 215. DUNN, A. J., AND H. E. CHULUYAN. The role of cyclooxygenase and lipoxygenase in the interleukin-1-induced activation of the HPA axis: dependence on the route of injection. Life Sci. 51: 219– 225, 1992. 216. DUNN, A. J., AND H. E. CHULUYAN. Endotoxin elicits normal tryptophan and indolamine responses but impaired catecholamine and pituitary-adrenal responses in endotoxin-resistant mice. Life Sci. 54: 847–853, 1994. 218. DUNN, A. J., M. L. POWELL, AND J. M. GASKIN. Virus-induced increases in plasma corticosterone. Science 238: 1423–1424, 1987. 11-25-98 11:16:36 pra APS-Phys Rev Downloaded from on April 23, 2014 186. REGULATION OF HPA AXIS BY CYTOKINES 50 ANDREW V. TURNBULL AND CATHERINE L. RIVIER / 9j0c$$oc11 P13-8 236. 237. 238. 239. 240. 241. 242. 243. 244. 245. 246. 247. 248. 249. 250. 251. 252. 253. 11-25-98 11:16:36 vation of stress-related neuroendocrine circuitry by intravenous interleukin-1. J. Neurosci. 17: 7166–7179, 1997. ERICSSON, A., M. EK, AND N. LINDEFORS. Distribution of prostaglandin E2 receptor (EP3 subtype) mRNA containing cells in the rat central nervous system. Soc. Neurosci. Abstr. 21: 45.9, 1995. ERICSSON, A., K. J. KOVACS, AND P. E. SAWCHENKO. A functional anatomical analysis of central pathways subserving the effects of interleukin-1 on stress-related neuroendocrine neurons. J. Neurosci. 14: 897–913, 1994. ERICSSON, A., C. LIU, R. P. HART, AND P. E. SAWCHENKO. Type I interleukin-1 receptor in the rat brain: distribution, regulation and relationship to sites of IL-1-induced cellular activation. J. Comp. Neurol. 361: 681–698, 1995. ERKUT, Z. A., M. A. HOFMAN, R. RAVID, AND D. F. SWAAB. Increased activity of hypothalamic corticotropin-releasing hormone neurons in multiple sclerosis. J. Neuroimmunol. 62: 27–33, 1995. ERNFORS, P., C. WETMORE, L. OLSON, AND H. PERSSON. Identification of cells in rat brain and peripheral tissues expressing mRNA for members of the nerve growth factor family. Neuron 5: 511–526, 1990. ESPEVICK, T., M. BROCKHAUS, H. LOETSCHER, U. NONSTAD, AND R. SHALABY. Characterization of binding and biological effects of monoclonal antibodies against a human tumor necrosis factor receptor. J. Exp. Med. 171: 415–426, 1990. FABRY, Z., K. M. FITZSIMMONS, J. A. HERLEIN, T. O. MONINGER, M. B. DOBBS, AND M. N. HART. Production of the cytokines interleukin-1 and 6 by murine brain microvessel endothelium and smooth muscle pericytes. J. Neuroimmunol. 47: 23–34, 1993. FAGARSON, M., R. ESKAY, AND J. AXELROD. Interleukin-1 potentiates the secretion of b endorphin induced by secretagogues in mouse pituitary cell line (AtT20). Proc. Natl. Acad. Sci. USA 86: 2070–2073, 1989. FAN, X., AND G. V. CHILDS. Epidermal growth factor and transforming growth factor-alpha messenger ribonucleic acids and their receptors in the rat anterior pituitary: localization and regulation. Endocrinology 136: 2284–2293, 1995. FAN, X., G. T. NAGLE, T. J. COLLINS, AND G. V. CHILDS. Differential regulation of epidermal growth factor and transforming growth factor-alpha messenger ribonucleic acid in the rat anterior pituitary and hypothalamus induced by stresses. Endocrinology 136: 873–880, 1995. FANTUZZI, G., F. BENIGNI, M. SIRONI, M. CONNI, M. CARELLI, L. CANTONNI, L. SHAPIRO, C. A. DINARELLO, J. D. SIPE, AND P. GHEZZI. Ciliary neurotrophic factor (CNTF) induces serum amyloid A, hypoglycemia and anorexia, and potentiates IL-1 induced corticosterone and IL-6 production in mice. Cytokine 7: 150–156, 1995. FANTUZZI, G., AND C. A. DINARELLO. The inflammatory response in interleukin-1b-deficient mice: comparison with other cytokinerelated knockout mice. J. Leukoc. Biol. 59: 489–493, 1996. FANTUZZI, G., G. KU, M. W. HARDING, D. J. LIVINGSTON, J. D. SIPE, K. KUIDA, R. A. FLAVELL, AND C. A. DINARELLO. Response to local inflammation of IL-1b-converting enzyme deficient mice. J. Immunol. 158: 1818–1824, 1997. FANTUZZI, G., A. J. PUREN, M. W. HARDING, D. J. LIVINGSTON, AND C. A. DINARELLO. Interleukin-18 regulation of interferon gamma production and cell proliferation as shown in interleukin1 beta converting enzyme (caspase-1) deficient mice. Blood 91: 2118–2125, 1998. FANTUZZI, G., H. ZHENG, R. FAGGIONI, F. BENIGNI, P. GHEZZI, J. D. SIPE, A. R. SHAW, AND C. A. DINARELLO. Effect of endotoxin in IL-1 beta-deficient mice. J. Immunol. 157: 291–296, 1996. FARRAR, W. L., P. L. KILIAN, M. R. RUFF, J. M. HILL, AND C. B. PERT. Visualization and characterization of interleukin 1 receptors in brain. J. Immunol. 139: 459–463, 1987. FARRAR, W. L., M. VINCOUR, AND J. M. HILL. In situ hybridization histochemistry localization of interleukin-3 mRNA in mouse brain. Blood 73: 137–140, 1989. FASSBENDER, K., R. SCHMIDT, R. MOSSNER, M. DAFFERTSHOFER, AND M. HENNERICI. Pattern of activation of the hypothalamic-pituitary-adrenal axis in acute stroke. Relation to acute con- pra APS-Phys Rev Downloaded from on April 23, 2014 219. DUNN, A. J., M. L. POWELL, C. MEITIN, AND P. A. SMALL. Virus infection as a stressor: influenza virus elevates plasma concentrations of corticosterone, and brain concentrations of MHPG and tryptophan. Physiol. Behav. 45: 591–594, 1989. 220. DUNN, A. J., M. L. POWELL, W. V. MORSEHEAD, J. M. GASKIN, AND N. R. HALL. Effects of Newcastle disease virus administration to mice on the metabolism of cerebral biogenic amines, plasma corticosterone, and lymphocyte proliferation. Brain Behav. Immun. 1: 216–230, 1987. 221. DUNN, A. J., AND S. L. VICKERS. Neurochemical and neuroendocrine responses to Newcastle disease virus administration in mice. Brain Res. 645: 103–112, 1994. 222. DUNN, A. J., AND J. WANG. Cytokine effects on CNS biogenic amines. Neuroimmunomodulation 2: 319–328, 1995. 223. EBISUI, O., J. FUKATA, N. MURAKAMI, H. KOBAYASHI, H. SEGAWA, S. MURO, I. HANAOKA, Y. NAITO, Y. MASUI, Y. OHMOTO, H. IMURA, AND K. NAKAO. Effect of IL-1 receptor antagonist and antiserum to TNF-a on LPS-induced plasma ACTH and corticosterone in rats. Am. J. Physiol. 266 (Endocrinol. Metab. 29): E986– E992, 1994. 224. EGUCHI, N., H. HAYASHI, Y. URADE, S. ITO, AND O. HAYAISHI. Central action of prostaglandin E2 and its methyl ester in the induction of hyperthermia after their systemic administration in urethane anesthetized rats. J. Pharmacol. Exp. Ther. 247: 671– 679, 1988. 225. EISENBERG, S. P., R. J. EVANS, W. P. AREND, E. VERDERBER, M. T. BREWER, C. H. HANNUM, AND R. C. THOMPSON. Primary structure and functional expression from complimentary DNA of a known interleukin-1 receptor antagonist. Nature 343: 341–346, 1990. 226. ELENKOV, I. J., K. KOVACS, E. DUDA, E. STARK, AND E. S. VIZI. Presynaptic inhibitory effect of TNF-a on the release of noradrenaline in isolated median eminence. J. Neuroimmunol. 43: 117–120, 1992. 227. ELENKOV, I. J., K. KOVACS, J. KISS, L. BERTOK, AND E. S. VIZI. Lipopolysaccharide is able to bypass corticotrophin-releasing factor in affecting plasma ACTH and corticosterone levels: evidence from rats with lesions of the paraventricular nucleus. J. Endocrinol. 133: 231–236, 1992. 228. EL-HUSSEINI, A., J. A. PATTERSON, AND R. P. SHIU. Basic fibroblast growth factor (bFGF) and two of its receptors, FGFR1 and FGFR2: gene expression in the rat brain during postnatal development as determined by quantitative RT-PCR. Mol. Cell. Endocrinol. 104: 191–200, 1994. 229. ELLISON, M. D., J. T. POVLISHOCK, AND R. E. MERCHANT. Blood-brain barrier dysfunction in cats following recombinant interleukin-2 infusion. Cancer Res. 47: 5765–5770, 1987. 230. ELMQUIST, J. K., M. R. ACKERMANN, K. B. REGISTER, R. B. RIMLER, L. R. ROSS, AND C. D. JACOBSON. Induction of fos-like immunoreactivity in the rat brain following Pasteurella multocida endotoxin administration. Endocrinology 133: 3054–3057, 1993. 231. ELMQUIST, J. K., C. D. BREDER, J. E. SHERIN, T. E. SCAMMELL, W. F. HICKEY, D. DEWITT, AND C. B. SAPER. Intravenous lipopolysaccharide induces cyclooygenase-like immunoreactivity in rat brain perivascular microglia and meningeal macrophages. J. Comp. Neurol. 381: 119–129, 1997. 232. ELMQUIST, J. K., T. E. SCAMMELL, C. D. JACOBSON, AND C. B. SAPER. Distribution of Fos-like immunoreactivity in the rat brain following intravenous lipopolysaccharide administration. J. Comp. Neurol. 371: 85–103, 1996. 233. ENGELMANN, H., H. HOLTMANN, C. BRALEBUSCH, Y. S. AVNIL, I. SAROV, Y. NOPHAR, E. HADAS, O. LEITNER, AND D. WALLACH. Antibodies to a soluble form of a tumor necrosis factor (TNF) receptor have TNF-like activity. J. Biol. Chem. 265: 14497– 14504, 1990. 234. ERICKSON, S. L., F. J. DE SAUVAGE, K. KIKLY, K. CARVERMOORE, S. PITTS-MEEK, N. GILLETT, K. C. F. SHEEHAN, R. D. SCHREIBER, D. V. GOEDDEL, AND M. W. MOORE. Decreased sensitivity to tumor necrosis factor but normal T-cell development in TNF receptor-2 deficient mice. Nature 372: 560–563, 1994. 235. ERICSSON, A., C. ARIAS, AND P. E. SAWCHENKO. Evidence for an intramedullary prostaglandin-dependent mechanism in the acti- Volume 79 January 1999 254. 255. 256. 257. 258. 259. 260. 262. 263. 264. 265. 266. 267. 268. 269. 270. fusional state, extent of brain damage, and clinical outcome. Stroke 25: 1105–1108, 1994. FATTORI, E., M. CAPPALLETTI, P. COASTA, C. SELLITTO, L. CANTONI, M. CARELLI, R. FAGGIONI, G. FANTUZZI, P. GHEZZI, AND V. POLI. Defective inflammatory response in interleukin-6 deficient mice. J. Exp. Med. 180: 1243–1250, 1994. FEIGE, J. J., C. COCHET, C. SAVONA, D. L. SHI, M. KERAMIDAS, G. DEFAYE, AND E. M. CHAMBAZ. Transforming growth factor beta 1: an autocrine regulator of adrenocortical steroidogenesis. Endocr. Res. 17: 267–279, 1991. FERNANDEZ-ALONSO, A., K. BENAMAR, M. SANCHIBRIAN, F. J. LOPEZ-VALUPUESTA, AND F. J. MINANO. Role of interleukin-1b, interleukin-6 and macrophage inflammatory protein-1b in prostaglandin E2-induced hyperthermia in rats. Life Sci. 59: 185– 190, 1996. FERNANDEZ-BOTRAN, R. Soluble cytokine receptors: their role in immunoregulation. FASEB J. 5: 2567–2571, 1991. FERRARA, N., J. WINER, AND W. J. HENZEL. Pituitary follicular cells secrete an inhibitor of aortic endothelial cell growth: identification as leukemia inhibitory factor. Proc. Natl. Acad. Sci. USA 89: 698–702, 1992. FERRER, I., S. ALCANTARA, J. BALLABRIGA, M. OLIVE, R. BLANCO, R. RIVERA, M. CARMONA, M. BERRUEZO, S. PITARCH, AND A. M. PLANAS. Transforming growth factor-alpha (TGF-alpha) and epidermal growth factor-receptor (EGF-R) immunoreactivity in normal and pathologic brain. Prog. Neurobiol. 49: 99–123, 1996. FERRETTI, M., V. CASINI-RAGGI, T. T. PIZARRO, S. P. EISENBERG, C. C. NAST, AND F. COMINELLI. Neutralization of endogenous IL-1 receptor antagonist exacerbates and prolongs inflammation in rabbit immune colitis. J. Clin. Invest. 94: 449–453, 1994. FLESHNER, M., L. E. GOEHLER, J. HERMAN, J. K. RELTON, S. F. MAIER, AND L. R. WATKINS. Interleukin-1 beta induced corticosterone elevation and hypothalamic NE depletion is vagally mediated. Brain Res. Bull. 37: 605–610, 1995. FLESHNER, M., L. SLIBERT, T. DEAK, L. E. GOEHLER, D. MARTIN, L. R. WATKINS, AND S. F. MAIER. TNF-alpha-induced corticosterone elevation but not serum protein or corticosteroid binding globulin reduction is vagally mediated. Brain Res. Bull. 44: 701–706, 1997. FONG, Y., K. J. TRACEY, L. L. MOLDAWER, D. G. HESSE, K. B. MANOGUE, J. S. KENNEY, A. T. LEE, G. C. KUO, A. C. ALLISON, S. F. LOWRY, AND A. CERAMI. Antibodies to cachectin/tumor necrosis factor reduce interleukin-1 beta and interleukin-6 appearance during lethal bacteremia. J. Exp. Med. 170: 1627–1633, 1989. FONTANA, A., E. WEBER, AND J.-M. DAYER. Synthesis of interleukin-1/endogenous pyrogen in the brain of endotoxin-treated mice: a step in fever induction? J. Immunol. 133: 1696–1698, 1984. FORSTERMANN, U., I. GATH, P. SCHWARZ, E. I. CLOSS, AND H. KLEINHART. Isoforms of nitric oxide synthase. Properties, cellular distribution and expressional control. Biochem. Pharmacol. 50: 1321–1332, 1995. FREI, K., K. NOHAVA, U. V. MALIPIERO, C. SCHWARDEL, AND A. FONTANA. Production of macrophage colony-stimulating factor by astrocytes and brain macrophages. J. Neuroimmunol. 40: 189–195, 1992. FRENCH, R. A., J. F. ZACHARY, R. DANTZER, L. S. FRAWLEY, R. CHIZZONITE, P. PARNET, AND K. W. KELLEY. Dual expression of p80 type I and p68 type II interleukin-1 receptors on anterior pituitary cells synthesizing growth hormone. Endocrinology 137: 4027–4036, 1996. FUKATA, J., T. USUI, Y. NAITOH, Y. NAKAI, AND H. IMURA. Effects of recombinant interleukin-1a, -1b, 2 and 6 on ACTH synthesis and release in mouse pituitary tumor cell line AtT20. J. Endocrinol. 122: 33–39, 1989. GABELLEC, M.-M., R. GRIFFAIS, G. FILLION, AND F. HAOUR. Expression of interleukin 1a, interleukin 1b and interleukin 1 receptor antagonist mRNA in mouse brain: regulation by bacterial lipopolysaccharide (LPS) treatment. Brain Res. Mol. Brain Res. 31: 122–130, 1995. GABELLEC, M.-M., R. GRIFFAIS, G. FILLION, AND F. HAOUR. Interleukin-1 receptors type I and type II in the mouse brain: / 9j0c$$oc11 P13-8 271. 272. 273. 274. 275. 276. 277. 278. 279. 280. 281. 282. 283. 284. 285. 286. 287. 288. 289. 11-25-98 11:16:36 51 kinetics of mRNA expressions after peripheral administration of bacterial lipopolysaccharide. J. Neuroimmunol. 66: 65–70, 1996. GABELLEC, M.-M., M. JAFARIAN-TEHRANI, R. GRIFFAIS, AND F. HAOUR. Interleukin-1 receptor accessory protein transcripts in the brain and spleen: kinetics after peripheral administration of bacterial lipopolysaccharide in mice. Neuroimmunomodulation 3: 304–309, 1996. GADIENT, R. A., A. LACHMUND, K. UNSICKER, AND U. OTTEN. Expression of interleukin-6 (IL-6) and IL-6 receptor mRNAs in rat adrenal medulla. Neurosci. Lett. 194: 17–20, 1995. GADIENT, R. A., AND U. OTTEN. Differential expression of interleukin-6 (IL-6) and interleukin-6 receptor (IL-6R) mRNAs in rat hypothalamus. Neurosci. Lett. 153: 13–16, 1993. GADIENT, R. A., AND U. OTTEN. Expression of interleukin-6 (IL6) and interleukin-6 receptor (IL-6R) mRNAs in rat brain during postnatal development. Brain Res. 637: 10–14, 1994. GAILLARD, R. C., D. TURNILL, P. SAPPINO, AND A. F. MULLER. Tumor necrosis factor alpha inhibits the hormonal response of the pituitary gland to hypothalamic releasing factors. Endocrinology 127: 101–106, 1990. GARTHWAITE, J., G. GARTHAITE, R. M. PALMER, AND S. MONCADA. NMDA receptor activation induces nitric oxide synthesis from arginine in rat brain slices. Eur. J. Pharmacol. 172: 413– 416, 1989. GATTI, S., AND T. BARTFAI. Induction of tumor necrosis factoralpha mRNA in the brain after peripheral endotoxin treatment: comparison with interleukin-1 family and interleukin-6. Brain Res. 624: 291–294, 1993. GAY, N. J., AND F. J. KEITH. Drosophila and IL-1 receptor. Nature 351: 355–356, 1991. GAYKEMA, R. P. A., I. DIJKSTRA, AND F. J. H. TILDERS. Subdiaphragmatic vagotomy suppresses endotoxin-induced activation of hypothalamic corticotropin-releasing hormone neurons and ACTH secretion. Endocrinology 136: 4717–4720, 1995. GAYLE, D., S. E. ILYIN, AND C. R. PLATA-SALAMAN. Interleukin1 receptor type I mRNA levels in brain regions from male and female rats. Brain Res. Bull. 42: 463–467, 1997. GAYLE, D., S. E. ILYIN, AND C. R. PLATA-SALAMAN. Central nervous system IL-1 beta system and neuropeptide Y mRNAs during IL-1 beta-induced anorexia in rats. Brain Res. Bull. 44: 311–317, 1997. GAYLE, M. A., J. E. SIMS, S. K. DOWER, AND J. L. SLACK. Monoclonal antibody 1994–01 (also known as ALVA 42) reported to recognize type II IL-1 receptor is specific for HLA-DR alpha and beta chains. Cytokine 6: 83–86, 1994. GEHR, F., R. GENTZ, M. BROCKHAUS, H. LOETSCHER, AND W. LESSIAUER. Both tumor necrosis factor receptor types mediate proliferative signals in human mononuclear cell activation. J. Immunol. 149: 911–917, 1992. GELLER, D. A., A. K. NUSSLER, M. DI SILVINO, C. J. LOWENSTEIN, R. A. SHAPIRO, S. C. WANG, R. L. SIMMONS, AND T. R. BILLIAR. Cytokines, endotoxin, and glucocorticoids regulate the expression of inducible nitric oxide synthase in hepatocytes. Proc. Natl. Acad. Sci. USA 90: 522–526, 1993. GEMMA, C., P. GHEZZI, AND M. G. DE SIMONI. Activation of the hypothalamic serotoninergic system by interleukin-1. Eur. J. Pharmacol. 209: 139–140, 1991. GERSHENWALD, J. E., Y. FONG, T. J. FAHEY, S. E. CALVANO, R. CHIZZONITE, P. L. KILIAN, S. F. LOWRY, AND L. L. MOLDAWER. Interleukin-1 receptor blockade attenuates the host inflammatory response. Proc. Natl. Acad. Sci. USA 87: 4966–4970, 1990. GHAYUR, T., S. BANERJEE, M. HUGUNIN, D. BUTLER, L. HERZOG, A. CARTER, L. QUINTAL, L. SEKUT, R. TALNIAN, M. PASKIND, W. WONG, R. KAMEN, D. TRACEY, AND H. ALLEN. Caspase-1 processes IFN-gamma-inducing factor and regulates LPS-induced IFN-gamma production. Nature 386: 619–623, 1997. GIBBS, R. B., J. T. MCCABE, C. R. BUCK, M. V. CHAO, AND D. W. PFAFF. Expression of NGF receptor in the rat forebrain detected with in situ hybridization and immunohistochemistry. Brain Res. Mol. Brain Res. 6: 275–287, 1989. GISSLINGER, H., T. SVOBODA, M. CLODI, B. GILLY, H. LUDWIG, L. HAVELEC, AND A. LUGER. Interferon-alpha stimulates the hy- pra APS-Phys Rev Downloaded from on April 23, 2014 261. REGULATION OF HPA AXIS BY CYTOKINES 52 290. 291. 292. 293. 294. 296. 297. 298. 299. 300. 301. 302. 303. 304. pothalamo-pituitary axis in vivo and in vitro. Neuroendocrinology 57: 489–495, 1993. GIVALOIS, L., J. DORNAND, M. MEKAOUCHE, M. D. SOLIER, A. F. BRISTOW, G. IXART, I. SIAUD, I. ASSENMACHER, AND G. BARBANEL. Temporal cascade of plasma level surges in ACTH, corticosterone, and cytokines in endotoxin-challenged rats. Am. J. Physiol. 267 (Regulatory Integrative Comp. Physiol. 36): R164– R170, 1994. GIVALOIS, L., S. GAILLET, M. MEKAOUCHE, G. IXART, A. F. BRISTOW, P. SIAUD, A. SZAFARCZYK, F. MALAVAL, I. ASSENMACHER, AND G. BARBANEL. Deletion of the ventral noradrenergic bundle obliterates the early ACTH response after systemic LPS, independently from the plasma IL-1b surge. Endocrine 3: 481–485, 1995. GIVALOIS, L., P. SIAUD, M. MEKAOUCHE, G. IXART, F. MALAVAL, I. ASSENMACHER, AND G. BARBANEL. Early hypothalamic activation of combined Fos and CRH41 immunoreactivity and of CRH41 release in push-pull cannulated rats after systemic endotoxin challenge. Mol. Chem. Pathol. 26: 171–186, 1995. GIVALOIS, L., P. SIAUD, M. MEKAOUCHE, G. IXART, F. MALAVAL, I. ASSENMACHER, AND G. BARBANEL. Involvement of central histamine in the early phase of ACTH and corticosterone responses to endotoxin in rats. Neuroendocrinology 63: 219–226, 1996. GOEHLER, L. E., C. R. BUSCH, N. TARTAGLIA, J. RELTON, D. SISK, S. F. MAIER, AND L. R. WATKINS. Blockade of cytokine induced conditioned taste aversion by subdiaphragmatic vagotomy: further evidence for vagal mediation of immune-brain communication. Neurosci. Lett. 185: 163–166, 1995. GOEHLER, L. E., R. P. A. GAYKEMA, F. J. H. TILDERS, S. F. MAIER, AND L. R. WATKINS. Localization of immune and inflammatory markers in the rat vagus nerve and liver hilus (Abstract). Proc. Annu. Meet. Soc. Neurosci. 26th Washington DC 1996, p. 43.9. GOEHLER, L. E., J. K. RELTON, D. DRIPPS, R. KIECHLE, N. TARTAGLIA, S. F. MAIER, AND L. R. WATKINS. Vagal paraganglia bind biotinylated interleukin-1 receptor antagonist: a possible mechanism for immune-to-brain communication. Brain Res. Bull. 43: 357–364, 1997. GOLDBACH, J.-M., J. ROTH, AND E. ZEISBERGER. Fever suppression by subdiaphragmatic vagotomy in guinea pigs depends on the route of pyrogen administration. Am. J. Physiol. 272 (Regulatory Integrative Comp. Physiol. 41): R675–R681, 1997. GONZALEZ, A. M., A. LOGAN, W. YING, D. A. LAPPI, M. BERRY, AND A. BAIRD. Fibroblast growth factor in the hypothalamo-pituitary axis: differential expression of fibroblast growth factor-2 and a high affinity receptor. Endocrinology 134: 2289–2297, 1994. GONZALEZ-HERNANDEZ, J. A., S. R. BORNSTEIN, M. EHRHART-BORNSTEIN, E. SPATH-SCHWALBE, G. JIRIKOWSKI, AND W. A. SCHERBAUM. Interleukin-6 messenger ribonucleic acid expression in human adrenal gland in vivo: new clue to a paracrine or autocrine regulation of adrenal function. J. Clin. Endocrinol. Metab. 79: 1492–1497, 1994. GONZALEZ-HERNANDEZ, J. A., M. EHRHART-BORNSTEIN, E. SPATH-SCHWALBE, W. A. SCHERBAUM, AND S. R. BORNSTEIN. Human adrenal cells express tumor necrosis factor-alpha messenger ribonucleic acid: evidence for paracrine control of adrenal function. J. Clin. Endocrinol. Metab. 81: 807–813, 1996. GOSPODAROWICZ, D., A. BAIRD, J. CHENG, G. M. LUI, F. ESCH, AND P. BOHLEN. Isolation of fibroblast growth factor from bovine adrenal gland: physiochemical and biological characterization. Endocrinology 118: 82–90, 1986. GOTTFIRES, C. G., J. BALLDIN, K. BLENNOW, G. BRANE, I. KARLSSON, B. REGLAND, AND A. WALLIN. Regulation of the hypothalamo-pituitary-adrenal axis in dementia disorders. Ann. NY Acad. Sci. 746: 336–343, 1994. GOTTSCHALL, P. E., K. KOVES, K. MIZUNO, I. TATSUNO, AND A. ARIMURA. Glucocorticoid upregulation of interleukin 1 receptor expression in a glioblastoma cell line. Am. J. Physiol. 261 (Endocrinol. Metab. 24): E362–E368, 1991. GREENFEDER, S. A., P. NUNES, L. KWEE, M. LABOW, R. A. CHIZZONITE, AND G. JU. Molecular cloning and characterization / 9j0c$$oc11 P13-8 305. 306. 307. 308. 309. 310. 311. 312. 313. 314. 315. 316. 317. 318. 319. 320. 321. 322. 11-25-98 11:16:36 Volume 79 of a second subunit of the interleukin 1 receptor complex. J. Biol. Chem. 270: 13757–13765, 1995. GROSS, P. M., AND A. WEINDL. Peering through the windows of the brain. J. Cereb. Blood Flow Metab. 7: 663–672, 1987. GROTHE, C., AND K. UNSICKER. Immunocytochemical mapping of basic fibroblast growth factor in the developing and adult rat adrenal gland. Histochemistry 94: 141–147, 1990. GU, Y., K. KUIDA, H. TSUTSUI, G. KU, K. HSIAO, M. A. FLEMING, N. HAYASHI, K. HIGASHINO, H. OKAMURA, K. NAKANISHI, M. KURIMOTO, T. TANIMOTO, R. A. FLAVELL, V. SATO, M. W. HARDING, D. J. LIVINGSTON, AND M. S. SU. Activation of interferongamma inducing factor mediated by interleukin-1 beta converting enzyme. Science 275: 206–209, 1997. GUTIERREZ, E. G., W. A. BANKS, AND A. J. KASTIN. Murine tumor necrosis factor alpha is transported from blood to brain in the mouse. J. Neuroimmunol. 47: 169–176, 1993. GUTIERREZ, E. G., W. A. BANKS, AND A. J. KASTIN. Blood-borne interleukin-1 receptor antagonist crosses the blood-brain barrier. J. Neuroimmunol. 55: 153–160, 1994. GWOSDOW, A. R., M. S. A. KUMAR, AND H. H. BODE. Interleukin1 stimulation of the hypothalamo-pituitary-adrenal axis. Am. J. Physiol. 258 (Endocrinol. Metab. 21): E65–E70, 1990. GWOSDOW, A. R., N. A. O’CONNELL, J. A. SPENCER, M. S. KUMAR, R. K. AGARWAL, H. H. BODE, AND A. B. ABOU-SAMRA. Interleukin-1 induced corticosterone release occurs by an adrenergic mechanism from rat adrenal gland. Am. J. Physiol. 263 (Endocrinol. Metab. 26): E461–E466, 1992. GWOSDOW, A. R., J. A. SPENCER, N. A. O’CONNELL, AND A. B. ABOU-SAMRA. Interleukin-1 activates protein kinase A and stimulates adrenocorticotropic hormone release from AtT20 cells. Endocrinology 132: 710–714, 1993. HACHMAN, M., N. CRISTAL, R. M. WHITE, S. SEGAL, AND R. N. APTE. Complementary organ expression of IL-1 vs. IL-6 and CSF1 activities in normal and LPS-injected mice. Cytokine 8: 21–31, 1996. HAGAN, P., S. POOLE, AND A. F. BRISTOW. Endotoxin-stimulated production of rat hypothalamic interleukin-1b in vivo and in vitro, measured by specific immunoradiometric assay. J. Mol. Endocrinol. 11: 31–36, 1993. HAGAN, P., F. TILDERS, S. POOLE, AND A. F. BRISTOW. Development of a two-site immunoradiometric assay for rat/human corticotropin-releasing factor. Application to the measurement of interleukin-1b-induced production of hypothalamic CRF in vitro. J. Immunol. Methods 160: 11–18, 1993. HANISCH, U.-K., S. LYONS, F. KIRCHOFF, C. NOLTE, AND H. KETTENMANN. Expression of a functional interleukin-15 receptor complex by microglial cells in culture (Abstract). Proc. Annu. Meet. Soc. Neurosci. 26th Washington DC 1996, p. 336.15. HANISCH, U. K., W. ROWE, S. SHARMA, M. J. MEANEY, AND R. QUIRION. Hypothalamic-pituitary-adrenal activity during chronic central administration of interleukin-2. Endocrinology 135: 2465– 2472, 1994. HANNUM, C. H., C. J. WILCOX, W. P. AREND, F. G. JOSLIN, D. J. DRIPPS, P. M. HEIMDAL, L. G. ARMES, A. SOMMER, S. P. EISENBERG, AND R. C. THOMPSON. Interleukin-1 receptor antagonist activity of a human interleukin-1 inhibitor. Nature 343: 336–340, 1990. HANSEN, M. K., AND J. M. KRUEGER. Subdiaphragmatic vagotomy blocks the sleep- and fever-promoting effects of interleukin1 beta. Am. J. Physiol. 273 (Regulatory Integrative Comp. Physiol. 42): R1246–R1253, 1997. HANSEN, M. K., P. TAISHI, Z. CHEN, AND J. M. KRUEGER. Vagotomy blocks the induction of interleukin-1 beta (IL-1beta) mRNA in the brain of rats in response to sytemic IL-1beta. J. Neurosci. 18: 2247–2253, 1998. HAOUR, F., E. BAN, G. MILON, D. BAMAN, AND G. FILLION. Brain interleukin-1 receptors: characterization and modulation after lipopolysaccharide injection. Prog. Neuroendocrinol. Immunol. 3: 201–208, 1990. HARBUZ, M. S., A. J. CHOVER-GONZALEZ, S. BISWAS, S. L. LIGHTMAN, AND H. S. CHOWDREY. Role of central catecholamines in the modulation of corticotrophin-releasing factor mRNA pra APS-Phys Rev Downloaded from on April 23, 2014 295. ANDREW V. TURNBULL AND CATHERINE L. RIVIER January 1999 323. 324. 325. 326. 327. 328. 329. 331. 332. 333. 334. 335. 336. 337. 338. 339. 340. 341. during adjuvant-induced arthritis. Br. J. Rheumatol. 33: 205–209, 1994. HARBUZ, M. S., G. L. CONDE, O. MARTI, S. L. LIGHTMAN, AND D. S. JESSOP. The hypothalamic-pituitary-adrenal axis in autoimmunity. Ann. NY Acad. Sci. 823: 214–224, 1997. HARBUZ, M. S., J. P. LEONARD, S. L. LIGHTMAN, AND M. L. CUZNER. Changes in hypothalamic corticotrophin-releasing factor and anterior pituitary pro-opiomelanocortin mRNA during the course of experimental allergic encephalomyelitis. J. Neuroimmunol. 45: 127–132, 1993. HARBUZ, M. S., R. G. REES, D. ECKLAND, D. S. JESSOP, D. BREWERTON, AND S. L. LIGHTMAN. Paradoxical responses of hypothalamic corticotropin-releasing factor (CRF) messenger ribonucleic acid (mRNA) and CRF-41 peptide and adenohypophysial proopiomelanocortin mRNA during chronic inflammatory stress. Endocrinology 130: 1394–1400, 1992. HARBUZ, M. S., A. STEPHANOU, R. A. KNIGHT, A. J. CHOVERGONZALEZ, AND S. L. LIGHTMAN. Action of interleukin-2 and interleukin-4 on CRF mRNA in the hypothalamus POMC mRNA in the anterior pituitary. Brain Behav. Immun. 6: 214–222, 1992. HARBUZ, M. S., A. STEPHANOU, N. SARLIS, AND S. L. LIGHTMAN. The effects of recombinant human interleukin (IL)1a, IL-1b or IL-6 on hypothalamo-pituitary-adrenal axis activation. J. Endocrinol. 133: 349–355, 1992. HARLIN, C. A., AND C. R. PARKER. Investigation of the effect of interleukin-1 beta on steroidogenesis in the human fetal adrenal gland. Steroids 56: 72–76, 1991. HASHIMOTO, K., T. NISHIOKA, C. TOJO, AND T. TAKAO. Nitric oxide plays no role in ACTH release induced by interleukin-1b, corticotropin-releasing hormone, arginine vasopressin and phorbol myristate acetate in rat pituitary cell cultures. Endocr. J. 42: 435–439, 1995. HASHIMOTO, M., Y. ISHIKAWA, S. YOKOTA, F. GOTO, F. BANDO, Y. SAKAKIBARA, AND M. IRIKI. Action of circulating interleukin-1 on the rabbit brain. Brain Res. 540: 217–223, 1991. HEALY, D. L., G. D. HODGEN, H. M. SCHULTE, G. P. CHROUSOS, D. L. LORIAUX, N. R. HALL, AND A. L. GOLDSTEIN. The thymusadrenal connection: thymosin has corticotropin-releasing activity in primates. Science 222: 1353–1355, 1983. HEANEY, M. L., AND D. W. GOLDE. Soluble cytokine receptors. Blood 87: 847–857, 1996. HELLE, M., J. P. BRAKENHOFF, E. R. DE GROOT, AND L. A. AARDEN. Interleukin-6 is involved in interleukin 1-induced activities. Eur. J. Pharmacol. 18: 957–959, 1988. HELLER, R. A., K. SONG, N. FAN, AND D. J. CHANG. The p70 tumor necrosis factor receptor mediates cytotoxicity. Cell 70: 47– 56, 1992. HENCH, P. S., E. C. KENDALL, C. H. SLOCUMB, AND H. F. POLLEY. The effect of a hormone of the adrenal cortex (17-hydroxycorticosterone: compound E) and of pituitary adrenocorticotropic hormone on rheumatoid arthritis. Mayo Clinic Proc. 24: 181–197, 1949. HERMUS, R. M., G. C. SWEEP, M. J. VAN DER MEER, H. A. ROSS, A. G. SMALS, T. J. BENRAAD, AND P. W. KLOPPENBORG. Continuous infusion of interleukin-1 beta induces a nonthyroidal illness syndrome in the rat. Endocrinology 131: 2139–2146, 1992. HERSEY, P., A. COATES, M. RALLINGS, C. HALL, M. MACDONALD, A. SPURLING, A. EDWARDS, W. H. MCCARTHY, AND G. W. MILTON. Comparative study on the effects of recombinant alpha2 interferon on immune function in patients with disseminated melanomas. J. Biol. Response Modif. 5: 236–249, 1986. HIGGINS, G. A., AND J. A. OLSCHOWKA. Induction of interleukin1b mRNA in adult rat brain. Brain Res. Mol. Brain Res. 9: 143– 148, 1991. HILLHOUSE, E. W. Interleukin-2 stimulates the secretion of arginine vasopressin but not corticotropin-releasing hormone from rat hypothalamic cells in vitro. Brain Res. 650: 323–325, 1994. HILLHOUSE, E. W., AND K. MOSLEY. Peripheral endotoxin induces hypothalamic immunoreactive interleukin-1 beta in the rat. Br. J. Pharmacol. 109: 289–290, 1993. HO, M. M., AND G. P. VINSON. Endocrine control of the distribution of basic fibroblast growth factor, insulin-like growth factor and transforming growth factor-b1 mRNAs in adult rat adrenals / 9j0c$$oc11 P13-8 342. 343. 344. 345. 346. 347. 348. 349. 350. 351. 352. 353. 354. 355. 356. 357. 358. 359. 360. 11-25-98 11:16:36 53 using non-radioactive in situ hybridization. J. Endocrinol. 144: 379–387, 1995. HOLSBOER, F., G. K. STALLA, U. VON BARDELEBEN, K. HAMMANN, H. MULLER, AND O. A. MULLER. Acute adrenocortical stimulation by recombinant gamma interferon in human controls. Life Sci. 42: 1–5, 1988. HOPKINS, S. J. Cytokines and their significance in rheumatic disease. In: Anti-rheumatic Drugs, edited by M. C. L. E. Orme. New York: Pergamon, 1990, p. 49–118. HOPKINS, S. J., AND N. J. ROTHWELL. Cytokines and the nervous system I: expression and regulation. Trends Neurosci. 18: 83–88, 1995. HORAN, M. A., R. A. LITTLE, N. J. ROTHWELL, AND P. J. L. M. STRIJBOS. Comparison of the effects of several endotoxin preparations on body temperature and metabolic rate in the rat. Can. J. Physiol. Pharmacol. 67: 1011–1014, 1989. HU, S.-B., L. A. TANNAHILL, AND S. L. LIGHTMAN. Interleukin1b induces corticotropin-releasing factor-41 release from cultured hypothalamic cells through protein kinase C and cAMP-dependent protein kinase pathways. J. Neuroimmunol. 40: 49–56, 1992. HU, Y., H. DIETRICH, M. HEROLD, P. C. HEINRICH, AND G. WICK. Disturbed immuno-endocrine communication via the hypothalamo-pituitary-adrenal axis in autoimmune disease. Int. Arch. Allergy Immunol. 102: 232–241, 1993. HUANG, J., X. GAO, S. LI, AND Z. CAO. Recruitment of IRAK to the interleukin-1 receptor complex requires interleukin 1 receptor accessory protein. Proc. Natl. Acad. Sci. USA 94: 12829–12832, 1997. HUETTNER, C., W. PAULUS, AND W. ROGGENDORF. Messenger RNA expression of the immunosuppressive cytokine IL-10 in human gliomas. Am. J. Pathol. 146: 317–322, 1995. HUGHES, T. K., P. CADET, P. L. RADY, S. K. TYRING, R. CHIN, AND E. M. SMITH. Evidence for the production and action of interleukin-10 in pituitary cells. Cell. Mol. Neurobiol. 14: 59–69, 1994. HUNTER, C. A., J. TIMANS, P. PISACANE, S. MENON, G. CAI, W. WALKER, M. ASTE-AMEZAGA, R. CHIZZONITE, J. F. BAZAN, AND R. A. KASTELEIN. Comparison of the effects of interleukin1 alpha, interleukin-1 beta and interferon-gamma-inducing factor on the production of interferon-gamma by natural killer. Eur. J. Immunol. 27: 2787–2792, 1997. ILYIN, S. E., AND C. R. PLATA-SALAMAN. An approach to study molecular mechanisms involved in cytokine-induced anorexia. J. Neurosci. Methods 70: 33–38, 1996. ILYIN, S. E., AND C. R. PLATA-SALAMAN. In vivo regulation of the IL-1b system (ligand, receptors I and II, receptor accessory protein and receptor antagonist) and TNF-a mRNAs in specific brain regions. Biochem. Biophys. Res. Commun. 227: 861–867, 1996. ILYIN, S. E., AND C. R. PLATA-SALAMAN. Molecular regulation of the brain interleukin-1 beta system in obese (fa/fa) and lean (Fa/ Fa) Zucker rats. Brain Res. Mol. Brain Res. 43: 209–218, 1996. ILYIN, S. E., AND C. R. PLATA-SALAMAN. HIV-1 envelope glycoprotein gp120 regulates brain IL-1 beta system and TNF-alpha mRNAs in vivo. Brain Res. Bull. 44: 67–73, 1997. ILYIN, S. E., AND C. R. PLATA-SALAMAN. HIV-1 gp120 glycoprotein modulates cytokine mRNAs in vivo: implications to cytokine feedback systems. Biochem. Biophys. Res. Commun. 231: 514– 518, 1997. ILYIN, S. E., G. SONTI, D. GAYLE, AND C. R. PLATA-SALAMAN. Regulation of brain interleukin-1b (IL-1b) system mRNAs in response to pathophysiological concentrations of IL-1b in the cerebrospinal fluid. J. Mol. Neurosci. 7: 169–181, 1996. IMURA, H., J.-I. FUKATA, AND T. MORI. Cytokines and endocrine function: an interaction between the immune and neuroendocrine systems. Clin. Endocrinol. 35: 107–115, 1991. ISHIZUKA, Y., Y. ISHIDA, T. KUNITAKE, K. KATO, T. HANAMORI, Y. MITSUYAMA, AND H. KANNAN. Effects of area postrema lesion and abdominal vagotomy on interleukin-1b-induced norepinephrine release in the hypothalamic paraventricular nucleus region in the rat. Neurosci. Lett. 223: 57–60, 1997. IWATA, H., A. MATSUYAMA, N. OKUMURA, S. YOSHIDA, Y. LEE, K. IMAIZUMI, AND S. SHIOSAKA. Localization of basic FGF-like pra APS-Phys Rev Downloaded from on April 23, 2014 330. REGULATION OF HPA AXIS BY CYTOKINES 54 361. 362. 363. 364. 365. 366. 367. 368. 370. 371. 372. 373. 374. 375. 376. 377. 378. 379. 380. immunoreactivity in the hypothalamo-hypophyseal neuroendocrine axis. Brain Res. 550: 329–332, 1991. JAATTELA, M., O. CARPEN, U. H. STENMAN, AND E. SAKSELA. Regulation of ACTH-induced steroidogenesis in human fetal adrenal glands by rTNF-alpha. Mol. Cell. Endocrinol. 68: R31–R36, 1990. JAATTELA, M., V. ILVESMAKI, R. VOUTILAINEN, U.-H. STENMAN, AND E. SAKSELA. Tumor necrosis factor as a potent inhibitor of adrenocorticotropin-induced cortisol production and steroidogenic P450 enzyme gene expression in cultured human fetal adrenal cells. Endocrinology 128: 623–629, 1991. JAFFE, H. L. The influence of the suprarenal gland on the thymus. III. Stimulation of the growth of the thymus gland following double suprarenalectomy in young rats. J. Exp. Med. 40: 753–760, 1924. JANICKI, P. K. Binding of human alpha-interferon in the brain tissue membranes of rat. Res. Commun. Chem. Pathol. Pharmacol. 75: 117–120, 1992. JANSKY, L., S. VYBIRAL, D. POPOSOLOVA, J. ROTH, J. DORNAND, E. ZEISBERGER, AND J. KAMINKOVA. Production of systemic and hypothalamic cytokines during the early phase of endotoxin fever. Neuroendocrinology 62: 55–61, 1995. JESSOP, D. S., AND S. L. LIGHTMAN. Priming of the anterior pituitary with corticotropin-releasing hormone in vitro does not facilitate an ACTH response to interleukin-1b. Immunol. Lett. 41: 225– 228, 1994. JOHANSSON, A., T. OLSSON, B. CALBERG, K. KARLSSON, AND M. FAGERLUND. Hypercortisolism after stroke: partly cytokine mediated? J. Neurol. Sci. 147: 43–47, 1997. JOHANSSON, B. B. The blood-brain barrier and perivascular cells. In: Immune Responses in the Nervous System, edited by N. J. Rothwell. Oxford, UK: Bios Scientific, 1995, p. 1–26. JOHNSON, A. K., AND P. M. GROSS. Sensory circumventricular organs and brain homeostatic pathways. FASEB J. 7: 678–686, 1993. JOHNSON, H. M., E. M. SMITH, B. A. TORRES, AND J. E. BLALOCK. Regulation of the in vitro antibody response by neuroendocrine hormones. Proc. Natl. Acad. Sci. USA 79: 4171–4174, 1982. JOHNSON, H. M., B. A. TORRES, E. M. SMITH, L. D. DION, AND J. E. BLALOCK. Regulation of lymphokine (gamma-interferon) production by corticotropin. J. Immunol. 132: 246–250, 1984. JOHNSON, R. W., S. ARKINS, R. DANTZER, AND K. W. KELLEY. Hormones, lymphohemopoietic cytokines and the neuroimmune axis. Comp. Biochem. Physiol. A Physiol. 116: 183–201, 1997. JOHNSON, R. W., G. GHEUSI, S. SEGRETI, R. DANTZER, AND K. W. KELLEY. C3H/HeJ mice are refractory to lipopolysaccharide in the brain. Brain Res. 752: 219–226, 1997. JONES, D. A., D. P. CARLTON, T. M. MCINTYRE, G. A. ZIMMERMAN, AND S. M. PRESCOTT. Molecular cloning of human prostaglandin endoperoxide synthase type II and demonstration of expression in response to cytokines. J. Biol. Chem. 268: 9049–9054, 1993. JONES, T. H., M. DANIELS, R. A. JAMES, S. K. JUSTICE, R. MCCORKLE, A. PRICE, P. KENDALL-TAYLOR, AND A. P. WEETMAN. Production of bioactive and immunoactive IL-6 and expression of IL-6 mRNA by human pituitary adenomas. J. Clin. Endocrinol. Metab. 78: 180–187, 1994. JONES, T. H., S. K. JUSTICE, A. PRICE, AND K. CHAPMAN. Interleukin-6 secreting human pituitary adenomas in vitro. J. Clin. Endocrinol. Metab. 73: 207–209, 1991. JONES, T. H., R. L. KENNEDY, S. K. JUSTICE, AND A. PRICE. Interleukin-1 stimulates the release of interleukin-6 from cultured human pituitary adenoma cells. Acta Endocrinol. 128: 405–410, 1993. JONES, T. H., R. L. KENNEDY, S. K. JUSTICE, AND A. PRICE. Pituitary adenomas with high and low basal inositol phospholipid turnover; the stimulatory effect of kinins and an association with interleukin-6 secretion. Clin. Endocrinol. 39: 433–439, 1993. JORDAN, M., I. G. OTTERNESS, R. NG, A. GESSNER, M. ROLLINGHOFF, AND H. U. BEUSCHER. Neutralization of endogenous IL-6 supresses induction of IL-1 receptor antagonist. J. Immunol. 154: 4081–4090, 1995. JOSEPH, J., J. L. GRUN, F. D. LUBLIN, AND R. L. KNOBLER. Cytokine induction in vitro in mouse brain endothelial cells and astro- / 9j0c$$oc11 P13-8 381. 382. 383. 384. 385. 386. 387. 388. 389. 390. 391. 392. 393. 394. 395. 396. 397. 398. 399. 11-25-98 11:16:36 Volume 79 cytes by exposure to mouse hepatitis virus (MHV-4, JHM). Adv. Exp. Med. Biol. 342: 443–448, 1993. JU, G., X. ZHANG, B.-Q. JIN, AND C.-S. HUANG. Activation of corticotropin-releasing factor-containing neurons in the paraventricular nucleus of the hypothalamus by interleukin-1 in the rat. Neurosci. Lett. 132: 151–154, 1991. JUDD, A. M., AND R. M. MACLEOD. Angiotensin II increases interleukin-6 release from rat adrenal glomerulosa cells. Prog. Neuroendocrinol. Immunol. 4: 240–247, 1991. JUDD, A. M., AND R. M. MACLEOD. Adrenocorticotropin increases interleukin-6 release from rat adrenal zona glomerulosa cells. Endocrinology 130: 1245–1254, 1992. JUDD, A. M., AND R. M. MACLEOD. Differential release of tumor necrosis factor and IL-6 from adrenal zona glomerulosa cells in vitro. Am. J. Physiol. 268 (Endocrinol. Metab. 31): E114–E120, 1995. JUDD, A. M., B. L. SPANGELO, AND R. M. MACLEOD. Rat adrenal zone glomerulosa cells produce interleukin-6. Prog. Neuroendocrinol. Immunol. 3: 282–292, 1990. KABIERSCH, A., A. DEL REY, C. G. HONEGGER, AND H. O. BESEDOVSKY. Interleukin-1 induces changes in norepinepherine metabolism in the rat brain. Brain Behav. Immun. 2: 267–274, 1988. KAKUCSKA, I., Y. QI, B. D. CLARK, AND R. M. LECHAN. Endotoxin-induced corticotropin-releasing hormone gene expression in the hypothalamic paraventricular nucleus is mediated centrally by interleukin-1. Endocrinology 133: 815–821, 1993. KANEKO, M., K. KANEKO, J. SHINSAKO, AND M. F. DALLMAN. Adrenal sensitivity to adrenocorticotropin varies diurnally. Endocrinology 109: 70–75, 1981. KAPAS, L., M. K. HANSEN, H. Y. CHANG, AND J. M. KRUEGER. Vagotomy attenuates but does not prevent the somnogenic and febrile effects of lipopolysaccharide in rats. Am. J. Physiol. 274 (Regulatory Integrative Comp. Physiol. 42): R406–R411, 1998. KAPCALA, L. P., J. R. HE, Y. GAO, J. O. PIEPER, AND L. J. DETOLLA. Subdiaphragmatic vagotomy inhibits intra-abdominal interleukin-1b stimulation of adrenocorticotropin secretion. Brain Res. 728: 247–254, 1996. KAR, S., J. G. CHABOT, AND R. QUIRION. Quantitative autoradiographic localization of [125I]insulin-like growth factor I, [125I]insulin-like growth factor II, and [125I]insulin receptor binding sites in developing and adult rat brain. J. Comp. Neurol. 333: 375–397, 1993. KARANTH, S., K. LYSON, M. C. AGUILA, AND S. M. MCCANN. Effects of luteinizing-hormone-releasing hormone, a-melanocytestimulating hormone, naloxone, dexamethasone and indomethacin on interleukin-2-induced corticotropin-releasing factor release. Neuroimmunomodulation 2: 166–173, 1995. KARANTH, S., K. LYSON, AND S. M. MCCANN. Role of nitric oxide in interleukin 2-induced corticotropin-releasing factor release from incubated hypothalami. Proc. Natl. Acad. Sci. USA 90: 3383– 3387, 1993. KARANTH, S., K. LYSON, AND S. M. MCCANN. Cyclosporin A inhibits interleukin-2-induced release of corticotropin-releasing hormone. Neuroimmunomodulation 1: 82–85, 1994. KARANTH, S., AND S. M. MCCANN. Anterior pituitary hormone control by interleukin-2. Proc. Natl. Acad. Sci. USA 88: 2961–2965, 1991. KATOH-SEMBA, R., Y. KAISHO, A. SHINTANI, M. NAGAHAMA, AND K. KATO. Tissue distribution and immunocytochemical localization of neurotrophin-3 in the brain and peripheral tissues of rats. J. Neurochem. 66: 330–337, 1996. KATSUURA, G., A. ARIMURA, K. KOVES, AND P. E. GOTTSCHALL. Involvement of organum vasculosum of lamina terminalis and pre-optic area in interleukin-1 beta-induced ACTH release. Am. J. Physiol. 258 (Endocrinol. Metab. 21): E163–E171, 1990. KATSUURA, G., P. E. GOTTSCHALL, AND A. ARIMURA. Identification of a high affinity receptor for interleukin-1 beta in rat brain. Biochem. Biophys. Res. Commun. 156: 61–67, 1988. KATSUURA, G., P. E. GOTTSCHALL, R. R. DAHL, AND A. ARIMURA. Adrenocorticotropin release induced by intracerebroventricular injection of recombinant human interleukin-1 in rats: pos- pra APS-Phys Rev Downloaded from on April 23, 2014 369. ANDREW V. TURNBULL AND CATHERINE L. RIVIER January 1999 400. 401. 402. 403. 404. 405. 406. 407. 409. 410. 411. 412. 413. 414. 415. 416. 417. 418. 419. sible involvement of prostaglandin. Endocrinology 122: 1773– 1779, 1988. KAWASAKI, M., Y. YOSHIHARA, M. YAMAJI, AND Y. WATANABE. Expression of prostaglandin endoperoxide synthase in rat brain. Brain Res. Mol. Brain Res. 19: 39–46, 1993. KEANE, K. M., D. A. GIEGEL, W. J. LIPINSKI, M. J. CALLAHAN, AND B. D. SHIVERS. Cloning, tissue expression and regulation of rat interleukin 1b converting enzyme. Cytokine 7: 105–110, 1995. KEHRER, P., D. TURNILL, J.-M. DAYER, A. F. MULLER, AND R. C. GAILLARD. Human recombinant interleukin-1a and -b, but not recombinant tumor necrosis factor a stimulate ACTH release from rat anterior pituitary cells in vitro in a prostaglandin E2 and cAMP independent manner. Neuroendocrinology 48: 160–166, 1988. KEIFER, R., AND G. W. KREUTZBERG. Gamma interferon-like immunoreactivity in the rat nervous system. Neuroscience 37: 725– 734, 1990. KELLER-WOOD, M. E., AND M. F. DALLMAN. Corticosteroid inhibition of ACTH secretion. Endocr. Rev. 5: 1–24, 1984. KELLER-WOOD, M. E., J. SHINSAKO, AND M. F. DALLMAN. Integral as well as proportional adrenal responses to ACTH. Am. J. Physiol. 245 (Regulatory Integrative Comp. Physiol. 14): R53– R59, 1983. KENNEDY, B. P., C.-C. CHAN, S. A. CULP, AND W. A. CROMLISH. Cloning and expression of rat prostaglandin endoperoxide synthase (cyclooxygenase)-2 cDNA. Biochem. Biophys. Res. Commun. 197: 494–500, 1993. KENNEDY, M. K., D. S. TORRANCE, K. S. PICHA, AND K. M. MOHLER. Analysis of cytokine mRNA expression in the central nervous sytem of mice with experimental autoimmune encephalomyelitis reveals that IL-10 mRNA expression correlates with recovery. J. Immunol. 149: 2496–2505, 1992. KENT, S., R. M. BLUTHE, K. W. KELLEY, AND R. DANTZER. Sickness behavior as a new target for drug development. Trends Pharmacol. Sci. 13: 24–28, 1992. KENT, S., J. L. BRET-DIBAT, K. W. KELLEY, AND R. DANTZER. Mechanisms of sickness-induced decreases in food-motivated behavior. Neurosci. Biobehav. Rev. 20: 171–175, 1996. KERAMIDAS, M., J. J. BOURGARIAT, E. TABONE, P. CORTICELLI, E. M. CHAMBAZ, AND J. J. FEIGE. Immunolocalization of transforming growth factor-beta 1 in the bovine adrenal cortex using antipeptide antibodies. Endocrinology 129: 517–526, 1991. KESHET, E., S. D. LYMAN, D. E. WILLIAMS, D. M. ANDERSON, N. A. JENKINS, N. G. COPELAND, AND L. F. PARADA. Embryonic RNA expression patterns of the c-kit receptor and its cognate ligand suggest multiple functional roles in mouse development. EMBO J. 10: 2425–2435, 1991. KILBOURN, R. G., AND P. BELLONI. Endothelial cell production of nitrogen oxides in response to interferon gamma in combination with tumor necrosis factor, interleukin-1, or endotoxin. J. Natl. Cancer Inst. 82: 772–776, 1990. KIM, K. S., C. A. WASS, A. S. CROSS, AND S. OPAL. Modulation of blood-brain-barrier permeability by tumor necrosis factor an antibody to tumor necrosis factor in the rat. Lymphokine Cytokine Res. 11: 293–298, 1992. KINOUCHI, K., G. BROWN, G. PASTERNAK, AND B. DONNER. Identification and characterization of receptors for tumor necrosis factor-alpha in the brain. Biochem. Biophys. Res. Commun. 18: 1532–1538, 1991. KISHIMOTO, T., S. AKIRA, M. NARAZAKI, AND T. TAGA. Interleukin-6 family of cytokines and gp130. Blood 86: 1243–1254, 1995. KISHIMOTO, T., T. TAGA, AND S. AKIRA. Cytokine signal transduction. Cell 76: 253–262, 1994. KITAMURA, H., A. KONNO, M. MORIMATSU, B. D. JUNG, K. KIMURA, AND M. SAITO. Immobilization stress increases hepatic IL6 expression in mice. Biochem. Biophys. Res. Commun. 238: 707– 711, 1997. KLIR, J. J., J. L. MCCLELLAN, AND M. J. KLUGER. Interleukin-1b causes the increase in anterior hypothalamic interleukin-6 during LPS-induced fever in rats. Am. J. Physiol. 266 (Regulatory Integrative Comp. Physiol. 35): R1845–R1848, 1994. KLIR, J. J., J. ROTH, Z. SZELENYI, J. L. MCCLELLAN, AND M. J. KLUGER. Role of hypothalamic interleukin-6 and tumor necrosis / 9j0c$$oc11 P13-8 420. 421. 422. 423. 424. 425. 426. 427. 428. 429. 430. 431. 432. 433. 434. 435. 436. 437. 11-25-98 11:16:36 55 factor-b in LPS fever in rat. Am. J. Physiol. 265 (Regulatory Integrative Comp. Physiol. 34): R512–R517, 1993. KLUGER, M. J. Fever: role of pyrogens and cryogens. Physiol. Rev. 71: 93–127, 1991. KNIGGE, U., A. KJAER, H. JORGENSEN, M. GARBARG, C. ROSS, A. ROULEAU, AND J. WARBERG. Role of hypothalamic histaminergic neurons in mediation of ACTH and beta-endorphin responses to LPS endotoxin in vivo. Neuroendocrinology 60: 243– 251, 1994. KOBAYASHI, H., J. FUKATA, N. MURAKAMI, T. USUI, O. EBISUI, S. MURO, I. HANAOKA, K. INOUE, H. IMURA, AND K. NAKAO. Tumor necrosis factor receptors in the pituitary cells. Brain Res. 758: 45–50, 1997. KOBAYASHI, H., J. FUKATA, T. TOMINAGA, N. MURAKAMI, M. FUKUSHIMA, O. EBISUI, H. SEGAWA, Y. NAKAO, AND H. IMURA. Regulation of interleukin-1 receptors on AtT-20 mouse pituitary tumour cells. FEBS Lett. 298: 100–104, 1992. KOENIG, J. I., K. SNOW, B. D. CLARK, R. TONI, J. G. CANNO, A. R. SHAW, C. A. DINARELLO, S. REICHLEIN, S. L. LEE, AND R. M. LECHAN. Intrinsic pituitary interleukin-1b is induced by bacterial lipopolysaccharide. Endocrinology 126: 3053–3058, 1990. KOH, S., G. A. OYLER, AND G. A. HIGGINS. Localization of nerve growth factor receptor messenger RNA and protein in the adult rat brain. Exp. Neurol. 106: 209–221, 1989. KOIKE, K., Y. SAKAMOTO, T. SAWADA, M. OHMICHI, Y. KANDA, A. NOHARA, K. HIROTA, H. KIYAMA, AND A. MIYAKE. The production of CINC/gro, a member of the interleukin-8 family, in rat anterior pituitary gland. Biochem. Biophys. Res. Commun. 202: 161–167, 1994. KOIV, L., E. MERISALU, K. ZILMER, T. TOMBERG, AND A. E. KAASIK. Changes of sympatho-adrenal and hypothalamo-pituitary-adrenocortical system in patients with head injury. Acta Neurol. Scand. 96: 52–58, 1997. KOJIMA, H., M. TAKEUCHI, T. OHTA, Y. NISHIDA, N. ARAI, M. IKEDA, H. IKEGAMI, AND M. KURIMOTO. Interleukin-18 activates the IRAK-TRAF6 pathway in mouse EL-4 cells. Biochem. Biophys. Res. Commun. 244: 183–186, 1998. KOMAKI, G., A. ARIMURA, AND K. KOVES. Effect of intravenous injection of IL-1b on PGE2 levels in several brain areas as determined by microdialysis. Am. J. Physiol. 262 (Endocrinol. Metab. 25): E246–E251, 1992. KONISHI, Y., D. H. CHIU, T. KUNISHITA, T. YAMAMURA, Y. HIGASHI, AND T. TABIRA. Demonstration of interleukin-3 receptorassociated antigen in the central nervous system. J. Neurosci. Res. 41: 572–582, 1995. KONONEN, J., S. SOINILA, H. PERSSON, J. HONANIEMI, T. KOKFELT, AND M. PELTO-HUIKKO. Neurotrophins and their receptors in the rat pituitary gland: regulation of BDNF and trkB mRNA levels by adrenal hormones. Brain Res. Mol. Brain Res. 27: 347– 354, 1994. KOPF, M., H. BAUMANN, G. FREER, M. FREUDENBERG, M. LAMERS, T. KISHIMOTO, R. ZINKERNAGEL, H. BLUETHMANN, AND G. KOHLER. Impaired immune and acute-phase responses in interleukin-6 deficient mice. Nature 368: 339–342, 1994. KORHERR, C., R. HOFMEISTER, H. WESCH, AND W. FALK. A critical role for interleukin-1 receptor accessory protein in interleukin-1 signaling. Eur. J. Immunol. 27: 262–267, 1997. KOVACS, K. J., AND I. J. ELENKOV. Differential dependence of ACTH secretion induced by various cytokines on the integrity of the paraventricular nucleus. J. Neuroendocrinol. 7: 15–23, 1995. KOVACS, K. J., A. FOLDES, AND E. S. VIZI. C-kit ligand (Stem Cell Factor) affects neuronal activity, stimulates pituitary-adrenal axis and prolactin secretion. J. Neuroimmunol. 65: 133–141, 1996. KOVACS, K. J., AND P. E. SAWCHENKO. Sequence of stress-induced alterations in indices of synaptic and transcriptional activation in parvocellular neurosecretory neurons. J. Neurosci. 16: 262–273, 1996. KOZAK, W., V. POLI, D. SOSZYNSKI, C. A. CONN, L. R. LEON, AND M. J. KLUGER. Sickness behavior in mice deficient in interleukin6 during turpentine abscess and influenza pneumonitis. Am. J. Physiol. 272 (Regulatory Integrative Comp. Physiol. 41): R621– R630, 1997. pra APS-Phys Rev Downloaded from on April 23, 2014 408. REGULATION OF HPA AXIS BY CYTOKINES 56 ANDREW V. TURNBULL AND CATHERINE L. RIVIER / 9j0c$$oc11 P13-8 458. 459. 460. 461. 462. 463. 464. 465. 466. 467. 468. 469. 470. 471. 472. 473. 474. 475. 11-25-98 11:16:36 in rats injected with interleukin-1 systemically or into the brain ventricles. J. Neuroendocrinol. 6: 217–224, 1994. LEE, S., AND C. RIVIER. Prenatal alcohol exposure alters the hypothalamic-pituitary-adrenal axis response of immature offspring to interleukin-1: is nitric oxide involved? Alcohol. Clin. Exp. Res. 18: 1242–1247, 1994. LEE, S., AND C. RIVIER. The intracerebroventricular injection of corticotropin-releasing factor or interleukin-1b increases mRNA levels of constitutive nitric oxide synthase in the rat hypothalamus (Abstract). Proc. Annu. Meet. Soc. Neurosci. 26th Washington DC 1996, p. 336. LEE, Y. B., J. SATOH, D. G. WALKER, AND S. U. KIM. Interleukin15 gene expression in human astrocytes and microglia in culture. Neuroreport 7: 1062–1066, 1996. LEMAY, L. G., I. G. OTTERNESS, A. J. VANDER, AND M. J. KLUGER. In vivo evidence that the rise in plasma IL-6 following injection of a fever-inducing dose of LPS is mediated by IL-1b. Cytokine 2: 199–204, 1990. LEMAY, L. G., A. J. VANDER, AND M. J. KLUGER. The effects of psychological stress on plasma interleukin-6 activity in rats. Physiol. Behav. 47: 957–961, 1990. LEON, L. R., M. GLACCUM, AND M. J. KLUGER. The IL-1 type I receptor mediates the acute phase response to turpentine, but not LPS, in mice. Am. J. Physiol. 271 (Regulatory Integrative Comp. Physiol. 40): R1668–R1674, 1996. LEON, S., R. S. CARROL, K. DASHNER, D. GLOWACKA, AND P. M. BLACK. Messenger ribonucleic acid expression of platelet-derived growth factor subunits and receptors in pituitary adenomas. J. Clin. Endocrinol. Metab. 79: 51–55, 1994. LESNIAK, M. A., J. M. HILL, W. KEIUSS, M. ROJESKI, C. B. PERT, AND J. ROTH. Receptors for insulin-like growth factors I and II: autoradiographic localization in rat brain and comparison to receptors for insulin. Endocrinology 123: 2089–2099, 1988. LEVINE, S., F. BERKENBOSCH, D. SUCHECKI, AND F. J. H. TILDERS. Pituitary-adrenal and interleukin-6 responses to recombinant interleukin-1 in neonatal rats. Psychoneuroendocrinology 19: 143– 153, 1994. LEWIS, M., L. A. TARTAGLIA, A. LEE, G. L. BENNET, G. C. RICE, G. H. W. WONG, E. Y. CHEN, AND D. V. GOEDDEL. Cloning and expression of cDNAs for two distinct murine tumor necrosis factor receptors demonstrate one receptor is species specific. Proc. Natl. Acad. Sci. USA 88: 2830–2834, 1991. LI, H.-Y., A. ERICSSON, AND P. E. SAWCHENKO. Distinct mechanisms underlie activation of hypothalamic neurosecretory neurons and their medullary catecholaminergic afferents in categorically different stress paradigms. Proc. Natl. Acad. Sci. USA 93: 2359–2364, 1996. LI, P., H. ALLEN, S. BANERJEE, S. FRANKLIN, L. HERZOG, C. JOHNSTON, J. MCDOWELL, M. PASKIND, L. RODMAN, J. SALFELD, E. TOWNE, D. TRACEY, S. WARDELL, F. Y. WEI, W. WONG, R. KAMEN, AND T. SESHADRI. Mice deficient in IL-1bconverting enzyme are defective in production of mature IL-1b and resistant to endotoxic shock. Cell 80: 401–411, 1995. LIBERT, C., P. BROUCKAERT, A. SHAW, AND W. FIERS. Induction of interleukin-6 by human and murine recombinant interleukin-1 in mice. Eur. J. Pharmacol. 20: 691–694, 1990. LICINIO, J., AND M.-L. WONG. Interleukin 1 receptor antagonist gene expression in rat pituitary in the systemic inflammatory response syndrome: pathological implications. Mol. Psychiatry 2: 99–103, 1997. LICINIO, J., M.-L. WONG, AND P. W. GOLD. Localization of interleukin-1 receptor antagonist mRNA in rat brain. Endocrinology 1991: 562–564, 1991. LICINIO, J., M.-L. WONG, AND P. W. GOLD. Neutrophil-activating pepide-1/interleukin-8 mRNA is localized in rat hypothalamus and hippocampus. Neuroreport 3: 753–756, 1992. LIND, R. W., G. W. VAN HOESEN, AND A. K. JOHNSON. An HRP study of the connections of the subfornical organ of the rat. J. Comp. Neurol. 210: 265–277, 1982. LINDOLM, D., E. CASTREN, M. BERZAGHI, A. BLOCHL, AND H. THOENEN. Activity-dependent and hormonal regulation of neurotrophin mRNA levels in the brain: implications for neuronal plasticity. J. Neurobiol. 25: 1362–1372, 1994. pra APS-Phys Rev Downloaded from on April 23, 2014 438. KOZAK, W., H. ZHENG, C. A. CONN, D. SOSZYNSKI, L. H. VAN DER PLOEG, AND M. J. KLUGER. Thermal and behavioral effects of lipopolysaccharide and influenza in interleukin-1 beta-deficient mice. Am. J. Physiol. 269 (Regulatory Integrative Comp. Physiol. 38): R969–R977, 1995. 439. KRUEGER, J. M. Somnogenic activity of immune response modifiers. Trends Pharmacol. Sci. 11: 122–126, 1990. 440. KRUEGER, J. M., AND J. A. MAJDE. Cytokines and sleep. Int. Arch. Allergy Immunol. 106: 97–100, 1995. 441. KUSHNER, I. The acute phase response: an overview. Methods Enzymol. 163: 373–383, 1988. 442. LABOW, M., D. SHUSTER, M. ZETTERSTOM, P. NUNES, R. TERRY, E. B. CULLINAN, T. BARTFAI, C. SOLORZANO, L. L. MOLDAWER, R. CHIZZONITE, AND K. W. MCINTYRE. Absence of IL-1 signalling and reduced inflammatory response in IL-1 type I receptor-deficient mice. J. Immunol. 159: 2452–2461, 1997. 443. LACROIX, S., AND S. RIVEST. Functional circuitry in the brain of immune-challenged rats: partial involvement of prostaglandins. J. Comp. Neurol. 387: 307–324, 1997. 444. LACROIX, S., AND S. RIVEST. Effect of acute systemic inflammatory response and cytokines on the transcription of the genes encoding cyclooxygenase enzymes (COX-1 and COX-2) in the rat brain. J. Neurochem. 70: 452–466, 1998. 445. LACROIX, S., L. VALLIERES, AND S. RIVEST. c-Fos mRNA pattern and CRF neuronal activity throughout the brain of rats injected centrally with a prostaglandin of E2 type. J. Neuroimmunol. 70: 163–179, 1996. 446. LANDGRAF, R., I. NEUMANN, F. HOLSBOER, AND Q. J. PITTMAN. Interleukin-1b stimulates both central and peripheral release of vasopressin and oxytocin in the rat. Eur. J. Neurosci. 7: 592–598, 1995. 447. LANGHANS, W., R. HARLACHER, G. BALKOWSKI, AND E. SCHARRER. Comparison of the effects of bacterial lipopolysaccharide and muramyl dipeptide on food intake. Physiol. Behav. 47: 805–813, 1990. 448. LAPCHAK, P. A., AND D. M. ARAUJO. Interleukin-2 regulates monoamine and opioid peptide release from the hypothalamus. Neuroreport 4: 303–306, 1993. 449. LASKIN, J. D., D. E. HECK, AND D. L. LASKIN. Multifunctional role of nitric oxide in inflammation. Trends Endocrinol. Metab. 5: 377– 382, 1994. 450. LAVICKY, J., AND A. J. DUNN. Endotoxin administration stimulates cerebral catecholamine release in freely moving rats as assessed by microdialysis. J. Neurosci. Res. 40: 407–413, 1995. 451. LAYE, S., R. M. BLUTHE, S. KENT, C. COMBE, C. MEDINA, P. PARNET, K. KELLEY, AND R. DANTZER. Subdiaphragmatic vagotomy blocks induction of IL-1 beta mRNA in mice brain in response to peripheral LPS. Am. J. Physiol. 268 (Regulatory Integrative Comp. Physiol. 37): R1327–R1331, 1995. 452. LAYE, S., E. GOUJON, C. COMBE, R. VANHOY, K. W. KELLY, P. PARNET, AND R. DANTZER. Effects of lipopolysaccharide and glucocorticoids on expression of interleukin-1 beta converting enzyme in the pituitary and brain of mice. J. Neuroimmunol. 68: 61–66, 1996. 453. LAYE, S., P. PARNET, E. GOUJON, AND R. DANTZER. Peripheral administration of lipopolysaccharide induces the expression of cytokine transcripts in the brain and pituitaries of mice. Brain Res. Mol. Brain Res. 27: 157–162, 1994. 454. LECHAN, R. M., R. TONI, B. D. CLARK, J. G. CANNON, A. R. SHAW, C. A. DINARELLO, AND S. REICHLIN. Immunoreactive interleukin-1b localization in the rat forebrain. Brain Res. 514: 135– 140, 1990. 455. LECHNER, O., Y. HU, M. JAFARIAN-TEHRANI, H. DIETRICH, S. SCHWARZ, M. HEROLD, F. HAOUR, AND G. WICK. Disturbed immunoendocrine communication via the hypothalamo-pituitaryadrenal axis in murine lupus. Brain Behav. Immun. 10: 337–350, 1996. 456. LEE, S., G. BARBANEL, AND C. RIVIER. Systemic endotoxin increases steady-state gene expression of hypothalamic nitric oxide synthase: comparison with corticotropin-releasing factor and vasopressin gene transcripts. Brain Res. 705: 136–148, 1995. 457. LEE, S., AND C. RIVIER. Hypophysiotropic role and hypothalamic gene expression of corticotropin-releasing factor and vasopressin Volume 79 January 1999 REGULATION OF HPA AXIS BY CYTOKINES / 9j0c$$oc11 P13-8 494. 495. 496. 497. 498. 499. 500. 501. 502. 503. 504. 505. 506. 507. 508. 509. 510. 511. 11-25-98 11:16:36 COMBE, P. GHIARA, AND N. J. ROTHWELL. Importance of brain IL-1 type II receptors in fever and thermogenesis in the rat. Am. J. Physiol. 265 (Endocrinol. Metab. 28): E585–E591, 1993. LUHESHI, G., A. J. MILLER, S. BROUWER, M. J. DASCOMBE, N. J. ROTHWELL, AND S. J. HOPKINS. Interleukin-1 receptor antagonist inhibits endotoxin fever and systemic interleukin-6 induction in the rat. Am. J. Physiol. 270 (Endocrinol. Metab. 33): E91– E95, 1995. LUHESHI, G. N., A. STEFFERL, A. V. TURNBULL, M. J. DASCOMBE, S. BROUWER, S. J. HOPKINS, AND N. J. ROTHWELL. Febrile response to tissue inflammation involves both peripheral and brain IL-1 and TNF-a in the rat. Am. J. Physiol. 272 (Regulatory Integrative Comp. Physiol. 41): R862–R868, 1997. LUSTIG, S., H. D. DANENBERG, Y. KAFRI, D. KOBILER, AND D. BEN-NATHAN. Viral neuroinvasion and encephalitis induced by lipopolysaccharide and its mediators. J. Exp. Med. 176: 707–712, 1992. LYMANGROVER, J. R., AND A. BRODISH. Tissue CRF: an extrahypothalamic corticotropihin releasing factor (CRF) in peripheral blood of stressed rats. Neuroendocrinology 12: 225–235, 1973. LYSON, K., AND S. M. MCCANN. The effect of interleukin-6 on pituitary hormone release in vivo and in vitro. Neuroendocrinology 54: 262–266, 1991. LYSON, K., AND S. M. MCCANN. Induction of adrenocorticotropic hormone release by interleukin-6 in vivo and in vitro. Ann. NY Acad. Sci. 650: 182–185, 1992. LYSON, K., AND S. M. MCCANN. Involvement of arachidonic cascade pathways in interleukin-6-stimulated corticotropin-releasing factor release in vitro. Neuroendocrinology 55: 708–713, 1992. LYSON, K., AND S. M. MCCANN. Alpha melanocyte-stimulating hormone abolishes IL-1 and IL-6-induced corticotropin-releasing factor release from the hypothalamus in vitro. Neuroendocrinology 58: 191–195, 1993. MA, Y. J., K. BERG-VON DER EMDE, M. MOHOLT-SIEBERT, D. F. HILL, AND S. R. OJEDA. Region-specific regulation of transforming growth factor a (TGFa) gene expression in astrocytes of the neuroendocrine brain. J. Neurosci. 14: 5644–5651, 1994. MA, Y. J., M. E. COSTA, AND S. R. OJEDA. Developmental expression of the genes encoding transforming growth factor alpha and its receptor in the hypothalamus of female rhesus macaques. Neuroendocrinology 60: 346–359, 1994. MA, Y. J., D. F. HILL, M. P. JUNIER, M. E. COSTA, S. E. FELDER, AND S. R. OJEDA. Expression of epidermal growth factor receptor changes in the hypothalamus during the onset of female puberty. Mol. Cell. Neurosci. 5: 246–262, 1994. MACKAY, F., J. ROTHE, H. BLUETHMANN, H. LOETSCHER, AND W. LESSLAUER. Differential responses of fibroblasts from wildtype and TNF-R55-deficient mice to mouse and human TNF-a activation. J. Immunol. 153: 5274–5284, 1994. MACKIEWICZ, A., M. WIZNEROWICZ, E. ROEB, A. KARCZEWSKA, J. NOWAK, P. C. HEINRICH, AND S. ROSE-JOHN. Soluble interleukin-6 receptor is biologically active in vivo. Cytokine 7: 142–149, 1995. MACKIEWICZ, M., P. J. SOLLARS, M. D. OGILVIE, AND A. J. PACK. Modulation of IL-1b gene expression in the rat CNS during sleep deprivation. Neuroreport 7: 529–533, 1996. MACLEOD, R. M., F. M. HUGHES, W. C. GOROSPE, AND B. L. SPANGELO. Synthesis, release, and actions of interleukin 6 in neuroendocrine tissues: methods and overview. Methods Neurosci. 17: 3–15, 1993. MACMICKING, J. D., C. NATHAN, G. HOM, N. CHARTRAIN, D. S. FLETCHER, M. TRUMBAUER, K. STEVENS, Q. W. XIE, K. SOKOL, AND N. HUTCHINSON. Altered response to bacterial infection and endotoxic shock in mice lacking inducible nitric oxide synthase. Cell 81: 641–650, 1995. MAES, M., E. BOSMANS, H. Y. MELTZER, S. SCHARPE, AND E. SUY. Interleukin-1 beta: a putatuve mediator of HPA axis hyperactivity in major depression? Am. J. Psychiatry 150: 1189–1193, 1993. MAIER, S. F., AND L. R. WATKINS. Intracerebroventricular interleukin-1 receptor antagonist blocks the enhancement of fear conditioning and interference with escape produced by inescapable shock. Brain Res. 695: 279–282, 1995. pra APS-Phys Rev Downloaded from on April 23, 2014 476. LING, C. R., AND M. A. FOSTER. Changes in NMR relaxation time associated with local inflammatory response. Phys. Med. Biol. 27: 853–859, 1982. 477. LINTHORST, A. C. E., C. FLACHSKAMM, F. HOLSBOER, AND J. M. H. M. REUL. Local administration of recombinant human interleukin-1b in the rat hippocampus increases serotonergic neurotransmission, hypothalamic-pituitary-adrenocortical axis activity and body temperature. Endocrinology 135: 520–533, 1994. 478. LINTHORST, A. C. E., C. FLACHSKAMM, F. HOLSBOER, AND J. M. H. M. REUL. Activation of serotonergic and adrenergic neurotransmission in the rat hippocampus after peripheral administration of bacterial endotoxin: involvement of cyclo-oxygenase pathway. Neuroscience 72: 989–997, 1996. 479. LISSONI, P., P. BARNI, F. ROVELLI, S. CRISPINO, G. FUMAGALLI, S. PESCIA, M. VAGHI, G. CAMESASCA, AND G. TANCINI. Neuroendocrine effects of subcutaneous interleukin-2 injection in cancer patients. Tumor 77: 212–215, 1991. 480. LISSONI, P., S. BARNI, E. TISI, F. ROVELLI, S. PITTALIS, R. RESCALDANI, L. VIGORE, A. BIONDI, A. ARDIZZOIA, AND G. TANCINI. In vivo biological results of the association between interleukin-2 and interleukin-3 in the immunotherapy of cancer. Eur. J. Cancer 29: 1127–1132, 1993. 481. LISSONI, P., F. ROVELLI, G. TANCINI, E. TISI, M. R. RIVOLTA, A. ARDIZZOIA, AND F. BRIVIO. Inhibitory effect on interleukin-3 on interleukin-2-induced cortisol release in the immunotherapy of cancer. J. Biol. Regul. Homeostasis Agents 6: 113–115, 1992. 482. LIU, C., D. CHALMERS, R. MAKI, AND E. B. DE SOUZA. Rat homolog of mouse interleukin-1 receptor accessory protein: cloning, localization and modulation studies. J. Neuroimmunol. 66: 41– 48, 1996. 483. LIU, L., T. KITA, N. TANAKA, AND Y. KINOSHITA. The expression of tumor necrosis factor in the hypothalamus after treatment with lipopolysaccharide. Int. J. Exp. Pathol. 77: 37–44, 1996. 484. LJUNGDAHL, A., T. OLSSON, P. H. VAN DER MEIDE, R. HOLMDAHL, L. KLARESKOG, AND B. HOJEBERG. Interferon-gammalike immunoreactivity in certain neurons of the central and peripheral nervous system. J. Neurosci. Res. 24: 451–456, 1989. 485. LODDICK, S. A., M.-L. WONG, P. B. BONGIORNO, P. W. GOLD, J. LICINIO, AND N. J. ROTHWELL. Endogenous interleukin-1 receptor antagonist is neuroprotective. Biochem. Biophys. Res. Commun. 234: 211–215, 1997. 486. LOGAN, A., AND M. BERRY. Transforming growth factor-b1 and basic fibroblast growth factor in the injured CNS. Trends Pharmacol. Sci. 14: 337–343, 1993. 487. LONG, N. C., I. OTTERNESS, S. L. KUNKEL, A. J. VANDER, AND M. J. KLUGER. The roles of interleukin-1b and tumor necrosis factor in lipopolysaccharide fever in rats. Am. J. Physiol. 259 (Regulatory Integrative Comp. Physiol. 28): R724–R728, 1990. 488. LORD, K. A., B. HOFFMAN-LIEBERMANN, AND D. A. LIEBERMANN. Nucleotide sequence and expression of a cDNA encoding MyD88, a novel myeloid differentiation primary response gene induced by IL6. Oncogene 5: 1095–1097, 1990. 489. LOVENBERG, T. W., P. D. CROWE, C. LIU, D. T. CHALMERS, X.-J. LIU, C. LIAW, W. CLEVENGER, T. OLTSERDORF, E. B. DE SOUZA, AND R. A. MAKI. Cloning of a cDNA encoding a novel interleukin-1 receptor related protein (IL-1R-rp2). J. Neuroimmunol. 70: 113–122, 1996. 490. LOWENTHAL, J. W., B. E. CASTLE, J. CHRISTIANSEN, J. SCHREURS, D. RENNICK, N. ARAI, P. HOY, Y. TAKEBE, AND M. HOWARD. Expression of high affinity receptors for murine interleukin-4 (BSF-1) on hemopoietic and nonhemopoietic cells. J. Immunol. 140: 456–464, 1988. 491. LOXLEY, H. D., A.-M. COWELL, R. J. FLOWER, AND J. C. BUCKINGHAM. Modulation of the hypothalamo-pituitary-adrenocortical responses to cytokines in the rat by lipocortin 1 and glucocorticoids: a role for lipocortin 1 in the feedback inhibition of CRF-41 release? Neuroendocrinology 57: 810–814, 1993. 492. LUGER, A., A. E. CALOGERO, K. KALOGERAS, W. T. GALLUCCI, P. W. GOLD, D. L. LORIAUX, AND G. P. CHROUSOS. Interaction of epidermal growth factor with the hypothalamo-pituitary-adrenal axis: potential physiologic relevance. J. Clin. Endocrinol. Metab. 66: 334–337, 1988. 493. LUHESHI, G., S. J. HOPKINS, R. A. LEFEUVRE, M. J. DAS- 57 58 ANDREW V. TURNBULL AND CATHERINE L. RIVIER / 9j0c$$oc11 P13-8 530. 531. 532. 533. 534. 535. 536. 537. 538. 539. 540. 541. 542. 543. 544. 545. 11-25-98 11:16:36 M. GIMENO, AND V. RETTORI. Induction by cytokines of the pattern of pituitary hormone secretion in infection. Neuroimmunomodulation 1: 2–13, 1994. MCCOY, J. G., S. G. MATTA, AND B. M. SHARP. Prostaglandins mediate the ACTH response to interleukin-1-beta instilled into the hypothalamic median eminence. Neuroendocrinology 60: 426– 435, 1994. MCEWAN, B. S., C. A. BIRON, K. W. BRUNSON, K. BULLOCH, W. H. CHAMBERS, F. S. DHABHAR, R. H. GOLDFARB, R. P. KITSON, A. H. MILLER, R. L. SPENCER, AND J. M. WEISS. The role of adrenocorticoids as modulators of immune function in health and disease: neural, endocrine and immune interactions. Brain Res. Rev. 23: 79–133, 1997. MCGILLIS, J. P., N. R. HALL, G. V. VAHOUNY, AND A. L. GOLDSTEIN. Thymosin fraction 5 causes increased serum corticosterone in rodents in vivo. J. Immunol. 134: 3952–3955, 1985. MCKELVIE, P. A., K. M. ROSEN, H. C. KINNEY, AND L. VILLAKOMAROFF. Insulin-like growth factor II expression in the developing human brain. J. Neuropathol. Exp. Neurol. 51: 464–471, 1992. MEFFORD, I. N., AND M. P. HEYES. Increased biogenic amine release in mouse hypothalamus following immunological challenge: antagonism by indomethacin. J. Neuroimmunol. 27: 55–61, 1990. MEGYERI, P., C. S. ABRAHA, P. TEMESVARI, J. KOVACS, T. VAS, AND C. P. SPEER. Recombinant tumor necrosis factor a constricts pial arterioles and increases blood-brain barrier permeability in newborn piglets. Neurosci. Lett. 148: 137–140, 1992. MEKAOUCHE, M., L. GIVALOIS, G. BARBANEL, P. SIAUD, D. MAUREL, A. F. BRISTOW, J. BOISSIN, I. ASSENMACHER, AND G. IXART. Chronic restraint enhances interleukin-1-beta release in the basal state and after an endotoxin challenge, independently of adrenocorticotropin and corticosterone release. Neuroimmunomodulation 1: 292–299, 1994. MESIANO, S., S. H. MELLON, D. GOSPODAROWICZ, A. M. DI BLASIO, AND R. B. JAFFE. Basic fibroblast growth factor expression is regulated by corticotropin in the human fetal adrenal: a model for adrenal growth regulation. Proc. Natl. Acad. Sci. USA 88: 5428–5432, 1991. MICHAELSON, M. D., M. F. MEHLER, H. XU, R. E. GROSS, AND J. A. KESSLER. Interleukin-7 is trophic for embryonic neurons and is expressed in developing brain. Dev. Biol. 179: 251–263, 1996. MICHELSON, D., L. STONE, E. GALLIVEN, M. A. MAGIAKOU, G. P. CHROUSOS, E. M. STERNBERG, AND P. W. GOLD. Multiple sclerosis is associated with alterations in hypothalamic-pituitaryadrenal axis function. J. Clin. Endocrinol. Metab. 79: 848–853, 1994. MILKENKOVIC, L., V. RETTORI, G. D. SNYDER, B. BEUTLER, AND S. M. MCCANN. Cachectin alters anterior pituitary hormone release by a direct action in vitro. Proc. Natl. Acad. Sci. USA 86: 2418–2422, 1989. MILLER, A. J., S. J. HOPKINS, AND G. N. LUHESHI. Sites of action of IL-1 in the development of fever and cytokine responses to tissue inflammation in the rat. Br. J. Pharmacol. 120: 1274–1279, 1997. MILLER, A. J., G. N. LUHESHI, N. J. ROTHWELL, AND S. J. HOPKINS. Local cytokine induction by LPS in the rat air pouch and its relationship to the febrile response. Am. J. Physiol. 272 (Regulatory Integrative Comp. Physiol. 41): R857–R861, 1997. MILLIGAN, E. D., M. M. MCGORRY, M. FLESHNER, R. P. GAYEKEMA, L. E. GOEHLER, L. R. WATKINS, AND S. F. MAIER. Subdiaphragmatic does not prevent fever following intracerebroventricular prostaglandin E2: further evidence for the importance of vagal afferents in immune-to-brain communication. Brain Res. 766: 240–243, 1997. MILTON, N. G., E. W. HILLHOUSE, AND A. S. MILTON. Activation of the hypothalamo-pituitary-adrenocortical axis in the conscious rabbit by the pyrogen polyinosinic: polycytidylic acid is dependent on corticotropihin-releasing factor-41. J. Endocrinol. 135: 69–75, 1992. MILTON, N. G., C. H. SELF, AND E. W. HILLHOUSE. Effects of pyrogenic immunomodulators on the release of corticotropin-re- pra APS-Phys Rev Downloaded from on April 23, 2014 512. MALARKEY, W. B., AND B. J. ZVARA. Interleukin-1b and other cytokines stimulate adrenocorticotropin release from cultured pituitary cells of patients with Cushing’s disease. J. Clin. Endocrinol. Metab. 69: 196–199, 1989. 513. MALIPIERO, U. V., K. FREI, AND A. FONTANA. Production of hemopoietic colony-stimulating factors by astrocytes. J. Immunol. 144: 3816–3821, 1990. 514. MANOVA, K., R. F. BACHVAROVA, E. J. HUANG, S. SANCHEZ, S. M. PRONOVOST, E. VELAZQUEZ, B. MCGURIE, AND P. BESMER. c-kit receptor and ligand expression in postantal development of the mouse cerebellum suggests a function for c-kit in inhibitory interneuons. J. Neurosci. 12: 4663–4676, 1992. 515. MARKS, J. L., D. PORTE, AND D. G. BASKIN. Localization of type I insulin-like growth factor receptor messenger RNA in the adult rat brain by in situ hybridization. Mol. Endocrinol. 5: 1158–1168, 1991. 516. MARQUETEE, C., A.-M. VAN DAM, E. CAN, P. LANIECE, M. CRUMEYROLLE-ARIAS, G. FILLION, F. BERKENBOSCH, AND F. HAOUR. Rat interleukin-1b binding sites in rat hypothalamus and pituitary gland. Neuroendocrinology 62: 362–369, 1995. 517. MARQUETTE, C., A.-M. VAN DAM, N. VAN ROOIJEN, F. BERKENBOSCH, AND F. HAOUR. Peripheral macrophage depletion prevents downregulation of central interleukin-1 receptors in mice after endotoxin administration. Psychoneuroendocrinology 19: 189–196, 1994. 518. MARTIN, F., AND J. BOYA. Immunocytochemical localization of basic fibroblast growth factor in the human pituitary gland. Neuroendocrinology 62: 523–529, 1995. 519. MASTORAKOS, G., G. P. CHROUSOS, AND J. S. WEBER. Recombinant interleukin-6 activates the hypothalamic-pituitary-adrenal axis in humans. J. Clin. Endocrinol. Metab. 77: 1690–1694, 1993. 520. MASTORAKOS, G., J. S. WEBER, M.-A. MAGIAKOU, H. GUNN, AND G. P. CHROUSOS. Hypothalamic-pituitary-adrenal axis activation and stimulation of systemic vasopressin secretion by recombinant interleukin-6 in humans: potential implications for the syndrome of inappropriate vasopressin secretion. J. Clin. Endocrinol. Metab. 79: 934–939, 1994. 521. MATHEWS, L. S., AND W. W. VALE. Expression cloning of an activin receptor, a predicted transmembrane serine kinase. Cell 65: 973–982, 1991. 522. MATSUMOTO, H., C. KOYAMA, T. SAWADA, K. KOIKE, A. MIYAKE, A. ARIMURA, AND K. INOUE. Pituitary folliculo-stellate-like cell line (TtT/GF) responds to novel hypophysiotropic peptide (pituitary adenylate cyclase activating peptide), showing increased 3*,5*-monophosphate and interleukin-6 secretion and cell proliferation. Endocrinology 133: 2150–2155, 1993. 523. MATSUMURA, K., Y. WATANABE, K. IMAI-MATSUMURA, M. CONNOLLY, Y. KOYAMA, H. ONOE, AND Y. WATANABE. Mapping of prostaglandin E2 binding sites in rat brain using quantitative autoradiography. Brain Res. 581: 292–298, 1992. 524. MATSUMURA, K., Y. WATANABE, H. ONOE, Y. WATANABE, AND O. HAYAISHI. High density of prostaglandin E2 binding sites in the anterior wall of the 3rd ventricle: a possible site of its hyperthermic action. Brain Res. 533: 147–151, 1990. 525. MATTA, S. G., K. M. LINNER, AND B. M. SHARP. Interleukin-1b and interleukin-1b stimulate adrenocorticotropin secretion in the rat through a similar hypothalamic receptor(s): effects of interleukin-1 receptor antagonist protein. Neuroendocrinology 57: 14–22, 1993. 526. MATTA, S. G., J. SINGH, R. NEWTON, AND B. M. SHARP. The adrenocorticotropin response to interleukin-1b instilled into the rat median eminence depends on the local release of catecholamines. Endocrinology 127: 2175–2182, 1990. 527. MATTA, S. G., J. WEATHERBEE, AND B. M. SHARP. A central mechanism is involved in the secretion of ACTH in response to IL-6 in rats: comparison to and interaction with IL-1b. Neuroendocrinology 56: 516–525, 1992. 528. MAZZOCCHI, G., F. G. MUSAJO, L. K. MALENDOWICZ, P. G. ANDREIS, AND G. G. NUSSDORFER. Interleukin-1b stimulates corticotropin-releasing hormone (CRH) and adrenocorticotropin (ACTH) release by rat adrenal gland in vitro. Mol. Cell. Neurosci. 79: 470–473, 1993. 529. MCCANN, S. M., S. KARANTH, A. KAMAT, W. L. DEES, K. LYSON, Volume 79 January 1999 546. 547. 548. 549. 550. 551. 552. 554. 555. 556. 557. 558. 559. 560. 561. 562. 563. leasing factor-41 and prostaglandin E2 from intact rat hypothalamus in vitro. Br. J. Pharmacol. 109: 88–93, 1993. MINAMI, M., Y. KURAISHI, T. YAMAGUCHI, S. NAKAI, Y. HIRAI, AND M. SATOH. Immobilization stress induces interleukin-1b mRNA in the rat hypothalamus. Neurosci. Lett. 123: 254–256, 1991. MINANO, F. J., A. FERNANDEZ-ALONSO, K. BENAMAR, R. K. MYERS, M. SANCIBRIAN, R. M. RUIZ, AND J. A. ARMENGOL. Macrophage inflammatory protein-1 beta (MIP-1 beta) produced endogenously in brain during E. coli fever in rats. Eur. J. Neurosci. 8: 424–428, 1996. MIRTELLA, A., G. TRINGALI, G. GUERRIERO, P. GHIARA, L. PARENTE, P. PREZIOSI, AND P. NAVARRA. Evidence that the interleukin-1b-induced prostaglandin E2 release from rat hypothalamus is mediated by type I and type II interleukin-1 receptors. J. Neuroimmunol. 61: 171–177, 1995. MISSALE, C., F. BORONI, S. SIGALA, A. BURIANI, M. FABRIS, A. LEON, R. DAL TOSO, AND P. SPANO. Nerve growth factor in the anterior pituitary: localization in mammotroph cells and cosecretion with prolactin by a dopamine-regulated mechanism. Proc. Natl. Acad. Sci. USA 93: 4240–4245, 1996. MITCHAM, J. L., P. PARNET, T. P. BONNERT, K. E. GARKA, M. J. GERHART, J. L. SLACK, M. A. GAYLE, S. K. DOWER, AND J. E. SIMS. T1/ST2 signaling establishes it as a member of an expanding interleukin-1 receptor family. J. Biol. Chem. 271: 5777–5783, 1996. MIYABO, S., E. OOYA, K. MIYANAGA, N. AOYAGI, M. HIRAI, S. KISHIDA, AND T. NAKAI. Stimulation of the hypothalamo-pituitary-adrenal axis by epidermal growth factor. Regul. Pept. 31: 65– 74, 1990. MIYAJIMA, A., T. KITAMURA, N. HARADA, T. YOKOTA, AND K.-I. ARAI. Cytokine receptors and signal transduction. Annu. Rev. Immunol. 10: 295–331, 1992. MOHANKUMAR, P. S., AND S. K. QUADRI. Systemic administration of interleukin-1 stimulates norepinephrine release in the paraventricular nucleus. Life Sci. 52: 1961–1967, 1993. MOHANKUMAR, P. S., S. THYAGARAJAN, AND S. KALEEM AUADRI. Interleukin-1 stimulates the release of dopamine and dihydroxyphenylacetic acid from the hypothalamus in vivo. Life Sci. 48: 925–930, 1991. MONCADA, S., R. M. J. PALMER, AND E. A. HIGGS. Nitric oxide: physiology, pathophysiology and pharmacology. Pharmacol. Rev. 43: 109–142, 1991. MONTGOMERY, D. W., J. A. LEFEVRE, E. D. ULRICH, C. R. ADAMSON, AND C. F. ZUKOSKI. Identification of prolactin-like proteins synthesized by normal murine lymphocytes. Endocrinology 127: 2601–2603, 1990. MONTGOMERY, D. W., C. F. ZUKOSKI, G. N. SHAH, A. R. BUCKLEY, T. PACHOLCZYK, AND D. H. RUSSEL. Concanavalin-A-stimulated murine splenocytes produce a factor with prolactin-like bioactivity and immunoreactivity. Biochem. Biophys. Res. Commun. 145: 692–698, 1987. MORGAN, J. I., AND T. CURRAN. Stimulus-transcription coupling in the nervous system: involvement of the inducible proto-oncogenes fos and jun. Annu. Rev. Neurosci. 14: 421–451, 1991. MORGANTI-KOSSMAN, M. C., T. KOSSMAN, AND S. M. WAHL. Cytokines and neuropathology. Trends Pharmacol. Sci. 13: 286– 291, 1992. MORIMOTO, A., N. MURAKAMI, T. NAKAMORI, Y. SAKATA, AND T. WATANABE. Possible involvement of prostaglandin E in development of ACTH response in rats induced by human recombinant interleukin-1. J. Physiol. (Lond.) 411: 245–256, 1989. MORROW, L. E., J. L. MCCLELLAN, C. A. CONN, AND M. J. KLUGER. Glucocorticoids alter fever and IL-6 responses to psychological stress and to lipopolysaccharide. Am. J. Physiol. 264 (Regulatory Integrative Comp. Physiol. 33): R1010–R1016, 1993. MOUIHATE, A., AND J. LESTAGE. Epidermal growth factor: a potential paracrine and autocrine system within the pituitary. Neuroreport 6: 1401–1404, 1995. MUCHAMUEL, T., S. MENON, P. PISACANE, M. C. HOWARD, AND D. A. COCKAYNE. IL-13 protects mice from lipopolysaccharideinduced lethal endotoxemia. Correlation with down-modulation of TNF-a, IFN-gamma and IL-12 production. J. Immunol. 158: 2898–2903, 1997. / 9j0c$$oc11 P13-8 59 564. MUELLER, S. G., AND J. E. KUDLOW. Transforming growth factorb (TGFb) inhibits TGFb expression in bovine anterior pituitaryderived cells. Mol. Endocrinol. 5: 1439–1446, 1991. 565. MULLER, H., E. HAMMES, C. HIEMKE, AND G. HESS. Interferonalpha-2-induced stimulation of ACTH and cortisol secretion in man. Neuroendocrinology 54: 499–503, 1991. 566. MULLER, H., C. HIEMKE, E. HAMMES, AND G. HESS. Sub-acute effects of interferon-alpha 2 on adrenocorticotrophic hormone, cortisol, growth hormone and prolactin in humans. Psychoneuroendocrinology 17: 459–465, 1992. 567. MUNCK, A., P. M. GUYRE, AND N. J. HOLBROOK. Physiological functions of glucocorticoids in stress and their relation to pharmacological actions. Endocr. Rev. 5: 25–44, 1984. 568. MURAKAMI, N. Function of the OVLT as an entrance into the brain for endogenous pyrogens. In: Neuroimmunology of Fever, edited by T. Bartfai and D. Ottoson. Oxford, UK: Pergamon, 1992, p. 107–114. 569. MURAKAMI, N., AND T. WATANABE. Activation of ACTH release is mediated by the same molecule as the final mediator, PGE2, of the febrile response in rats. Brain Res. 478: 171–174, 1989. 570. MURAMAMI, N., J. FUKATA, T. TSUKADA, H. KOBAYASHI, O. EBISUI, H. SEGAWA, S. MURO, H. IMURA, AND K. NAKAO. Bacterial lipopolysaccharide-induced expression of interleukin-6 messenger ribonucleic acid in the rat hypothalamus, pituitary, adrenal gland, and spleen. Endocrinology 133: 2574–2578, 1993. 571. MURROS, K., R. FOGELHOLM, S. KETTUNEN, AND A. L. VUORELA. Serum cortisol and outcome of ischemic brain infarction. J. Neurol. Sci. 116: 12–17, 1993. 572. NAITO, Y., J. FUKATA, Y. MASUI, Y. HIRAI, N. MURAKAMI, T. TOMINAGA, Y. NAKAI, S. TAMAI, K. MORI, AND H. IMURA. interleukin-1b analogues with markedly reduced pyrogenic activity can stimulate secretion of adrenocorticotropic hormone in rats. Biochem. Biophys. Res. Commun. 167: 103–109, 1990. 573. NAITO, Y., J. FUKATA, S. NAKAISHI, Y. NAKAI, Y. HIRAI, S. TAMAI, K. MORI, AND H. IMURA. Chronic effects of interleukin1 on hypothalamus, pituitary and adrenal glands in rat. Neuroendocrinology 51: 637–641, 1990. 574. NAITO, Y., J. FUKATA, T. TOMINAGA, Y. MASUI, Y. HIRAI, N. MURAKAMI, S. TAMAI, AND H. IMURA. Adrenocorticotropic hormone releasing activities of interleukins in a homologous in vivo system. Biochem. Biophys. Res. Commun. 164: 1262–1267, 1989. 575. NAITOH, Y., J. FUKATA, T. TOMINAGA, Y. NAKAI, S. TAMAI, K. MORI, AND H. IMURA. Interleukin-6 stimulates the secretion of adrenocorticotropic hormone in conscious, freely moving rats. Biochem. Biophys. Res. Commun. 155: 1459–1463, 1988. 576. NAKAMORI, T., A. MORIMOTO, K. YAMAGUCHI, T. WATANABE, N. C. LONG, AND N. MURAKAMI. Organosum vasculosum laminae terminalis (OVLT) is a brain site to produce interleukin-1b during fever. Brain Res. 618: 155–159, 1993. 577. NAKAMORI, T., A. MORIMOTO, K. YAMAGUCHI, T. WATANABE, AND N. MURAKAMI. Interleukin-1 beta production in the rabbit brain during endotoxin-induced fever. J. Physiol. (Lond.) 476: 177–186, 1994. 578. NAKAMORI, T., Y. SAKATA, T. WATANABE, A. MORIMOTO, S. NAKAMURA, AND N. MURAKAMI. Suppression of interleukin-1 beta production in the circumventricular organs in endotoxintolerant rabbits. J. Physiol. (Lond.) 675: 103–109, 1995. 579. NASH, A. D., M. R. BRANDON, AND P. A. BELLO. Effects of tumor necrosis factor-a on growth hormone and interleukin-6 mRNA in ovine pituitary cells. Mol. Cell. Endocrinol. 84: R31–R37, 1992. 580. NASUSHITA, R., H. WATANOBE, AND K. TAKEBE. A comparative study of adrenocorticotropin-releasing activity of prostaglandins E1, E2, F2a and D2 in the rat. Prostaglandins Leukotrienes Essent. Fatty Acids 56: 165–168, 1997. 581. NAVARRA, P. The effects of endotoxin on the neuroendocrine axis. Curr. Opin. Endocrinol. Diabetes 2: 127–133, 1995. 582. NAVARRA, P., G. POZZOLI, L. BRUNETTI, E. RAGAZZONI, M. BESSER, AND A. GROSSMAN. Interleukin-1b and interleukin-6 specifically increase the release of prostaglandin E2 from rat hypothalamic explants in vitro. Neuroendocrinology 56: 61–68, 1992. 583. NAVARRA, P., S. TSAGARAKIS, M. FARIA, L. H. REES, G. M. BESSER, AND A. B. GROSSMAN. Interleukins-1 and -6 stimulate the release of corticotropin-releasing hormone-41 from rat hypothala- 11-25-98 11:16:36 pra APS-Phys Rev Downloaded from on April 23, 2014 553. REGULATION OF HPA AXIS BY CYTOKINES 60 584. 585. 586. 587. 588. 589. 590. 592. 593. 594. 595. 596. 597. 598. 599. 600. mus in vitro via the eicosanoid cyclooxygenase pathway. Endocrinology 128: 37–44, 1991. NETA, R., R. PERLSTEIN, S. N. VOGEL, G. D. LEDNEY, AND J. ABRAHAMS. Role of interleukin-6 (IL-6) in the protection from lethal irradiation and in endocrine responses to IL-1 and tumor necrosis factor. J. Exp. Med. 175: 689–694, 1992. NIETFELD, J. J., B. WILLBRINK, M. HELLE, J. L. VAN ROY, W. DEN OTTER, A. J. SWAAK, AND O. HUBER-BRUNING. Interleukin-1-induced interleukin-6 is required for the inhibition of proteoglycan synthesis by interleukin-1 in human articular carilage. Arthritis Rheum. 33: 1695–1701, 1990. NIIJIMA, A. The afferent discharges from sensors for interleukin1b in the hepato-portal system in the rat (Abstract). J. Physiol. (Lond.) 446: 236P, 1992. NIIJIMA, A. The afferent discharges from sensors for interleukin 1 beta in the hepatoportal system in the anesthetized rat. J. Auton. Nerv. Syst. 61: 287–291, 1996. NIIMI, M., M. SAT, Y. WADA, J. TAKAHARA, AND K. KAWANISHI. Effect of central and continuous intravenous injection of interleukin-1b on brain c-fos expression in the rat: involvement of prostaglandins. Neuroimmunomodulation 3: 87–92, 1996. NIIMI, M., Y. WADA, M. SATO, J. TAKAHARA, AND K. KAWANISHI. Effect of continuous intravenous injection of interleukin-6 and pretreatment with cyclooxygenase inhibitor on brain c-fos expression in the rat. Neuroendocrinology 66: 47–53, 1997. NISHIBORI, M., N. NAKAYA, A. TAHARA, M. KAWABATA, S. MORI, AND K. SAEKI. Presence of macrophage migration factor (MIF) in ependyma, astrocytes and neurons in the bovine brain. Neurosci. Lett. 213: 193–196, 1996. NISHINO, T., J. BERNHAGEN, H. SHIIKI, T. CALANDRA, K. DOHI, AND R. BUCALA. Localization of macrophage migration inhibitory factor (MIF) to secretory granules within the corticotrophic and thyrotrophic cells of the pituitary gland. Mol. Med. 1: 781–788, 1995. NISHIYORI, A., M. MINAMI, S. TAKAMI, AND M. SATOH. Type 2 interleukin-1 receptor mRNA is induced by kainic acid in the rat brain. Brain Res. 50: 237–245, 1997. NITTA, T., K. SATO, M. ALLEGRETTA, S. BROCKE, M. LIM, D. J. MITCHELL, AND L. STEINMAN. Expression of granulocyte colony stimulating factor and granulocyte-macrophage colony stimulating factor genes in human astrocytoma cell lines and in glioma specimens. Brain Res. 571: 19–25, 1992. NOBEL, C. S., AND M. SCHULTZBERG. Induction of interleukin1b mRNA and enkephalin mRNA in the rat adrenal gland by lipopolysaccharides studied by in situ hybridization histochemistry. Neuroimmunomodulation 2: 61–73, 1995. NOHAVA, K., U. MALIPIERO, K. FREI, AND A. FONTANA. Neurons and neuroblastoma as a source of macrophage colony-stimulating factor. Eur. J. Immunol. 22: 2539–2545, 1992. NOLTEN, W. E., D. GOLDSTEIN, M. LINDSTROM, M. V. MCKENNA, I. H. CARLSON, D. L. TRUMP, J. SCHILLER, E. C. BORDEN, AND E. N. EHRLICH. Effects of cytokines on the pituitaryadrenal axis in cancer patients. J. Interferon Res. 13: 349–357, 1993. O’CONNELL, N. A., A. KUMAR, K. CHATZIPANTELI, A. MOHAN, R. K. AGARWAL, C. HEAD, S. R. BORNSTEIN, A. B. ABOU-SAMARA, AND A. R. GWOSDOW. Interleukin-1 regulates corticosterone secretion from the rat adrenal gland through a catecholamine-dependent and prostaglandin E2-independent mechanism. Endocrinology 135: 460–467, 1994. O’GRADY, M. P., N. R. S. HALL, AND R. A. MENZIES. Interleukin1b stimulates adrenocorticotropin and corticosterone release in 10-day-old rat pups. Psychoneuroendocrinology 18: 241–247, 1993. OHGO, S., K. NAKATSURU, E. ISHIKAWA, AND S. MATSUKURA. Interleukin-1 (IL-1) stimulates the release of corticotropin-releasing factor (CRF) from superfused rat hypothalamo-neurohypophyseal complexes (HNC) independently of the histaminergic mechanism. Brain Res. 558: 217–223, 1991. OHGO, S., K. NAKATSURU, Y. OKI, E. ISHIKAWA, AND S. MATSUKURA. Stimulation by interleukin-1 (IL-1) of the release of rat corticotropin-releasing factor (CRF), which is independent of the / 9j0c$$oc11 P13-8 601. 602. 603. 604. 605. 606. 607. 608. 609. 610. 611. 612. 613. 614. 615. 616. 617. 618. 619. 11-25-98 11:16:36 Volume 79 cholinergic mechanism, from superfused rat hypothalamo-neurohypophysial complexes. Brain Res. 550: 213–219, 1991. OHMICHI, M., K. HIROTA, K. KOIKE, H. KURACHI, S. OHTSUKA, N. MATSUZAKI, M. YAMAGUCHI, A. MIYAKE, AND O. TANIZAWA. Binding sites for interleukin-6 in the anterior pituitary gland. Neuroendocrinology 55: 199–203, 1992. OHZATO, H., M. MONDEN, K. YOSHIZAKI, A. OGATA, N. NISHIMOTO, M. GOTOH, T. KISHIMOTO, AND T. MORI. Systemic production of interleukin-6 following acute inflammation in the rat. Biochem. Biophys. Res. Commun. 197: 1556–1562, 1993. OLDENBURG, H. S. A., M. A. ROGY, D. D. LAZARUS, K. J. VAN ZEE, B. P. KEELER, R. A. CHIZZONITE, S. F. LOWRY, AND L. L. MOLDAWER. Cachexia and the acute-phase protein response in inflammation are regulated by interleukin-6. Eur. J. Immunol. 23: 1889–1894, 1993. OLSEN, N. J., W. E. NICHOLSON, C. R. DEBOLD, AND D. N. ORTH. Lymphocyte-derived adrenocorticotropin is insufficient to stimulate adrenal steroidogenesis in hypophysectomized rats. Endocrinology 130: 2113–2119, 1992. OPP, M. R., AND J. M. KRUEGER. Anti-interleukin-1b reduces sleep and sleep rebound after sleep deprivation in rats. Am. J. Physiol. 266 (Regulatory Integrative Comp. Physiol. 35): R688– R695, 1994. OPP, M. R., AND J. M. KRUEGER. Interleukin-1 is involved in responses to sleep deprivation in the rabbit. Brain Res. 639: 57–65, 1994. OPP, M. R., AND L. A. TOTH. Somnogenic and pyrogenic effects of interleukin-1beta and lipopolysaccharide in intact and vagotomized rats. Life Sci. 62: 923–936, 1998. ORANGE, J. S., T. P. SALAZAR-MATHER, S. M. OPAL, R. L. SPENCER, A. H. MILLER, B. S. MCEWAN, AND C. A. BIRON. Mechanism of interleukin-12-mediated toxicities during experimental viral infections: role of tumor necrosis factor and glucocorticoids. J. Exp. Med. 181: 901–914, 1995. O’SULLIVAN, M. G., F. H. CHILTON, E. M. HUGGINS, AND C. E. MCCALL. Lipopolysaccharide priming of alveolar macrophages for enhanced synthesis of prostanoids involves induction of a novel prostaglandin H synthase. J. Biol. Chem. 267: 14547–14550, 1992. OTA, K., T. KATAFUCHI, A. TAKAKI, AND T. HORI. AV3V neurons that send axons to hypothalamic nuclei respond to the systemic injection of IL-1b. Am. J. Physiol. 272 (Regulatory Integrative Comp. Physiol. 41): R532–R540, 1997. OTT, L., B. YOUNG, AND C. MCCLAIN. The metabolic response to brain injury. J. Parenterol. Enteral Nutr. 11: 488–493, 1987. OTTAVIANI, E., E. CASELGRANDI, AND C. FRANCESCHI. Cytokines and evolution: in vitro effects of IL-1 alpha, IL-1 beta, TNFalpha and TNF-beta on the ancestral type of stress response. Biochem. Biophys. Res. Commun. 207: 288–292, 1995. OTTAVIANI, E., E. CASELGRANDI, F. PETRAGLIA, AND C. FRANCESCHI. Stress response in the freshwater snail Planobarius corneus (L.) (gastropoda, pulmonata): interaction between CRF, ACTH, and biogenic amines. Gen. Comp. Endocrinol. 87: 354– 360, 1992. OTTAVIANI, E., A. COSSARIZZA, C. ORTOLANI, D. MONTI, AND C. FRANCESCHI. ACTH-like molecules in gastropod molluscs: a possible role in ancestral immune response and stress. Proc. R. Soc. Lond. B Biol. Sci. 245: 215–218, 1991. OTTAVIANI, E., AND C. FRANCHESCHI. The neuroimmunology of stress from invertebrates to man. Prog. Neurobiol. 48: 421–440, 1996. OTTAVIANI, E., AND C. FRANCHESCHI. The invertebrate phagocytic immunocyte: clues to a common evolution of immune and neuroendocrine systems. Immunol. Today 18: 169–174, 1997. OTTAVIANI, E., A. FRANCHINI, E. CASELGRANDI, A. COSSARIZZA, AND C. FRANCESCHI. Relationship between corticotropinreleasing factor and interleukin-2: evolutionary evidence. FEBS Lett. 351: 19–21, 1994. OTTEN, U., J. B. BAUMANN, AND J. GIRARD. Stimulation of the pituitary-adrenocortical axis by nerve growth factor. Nature 282: 412–414, 1979. OVADIA, H., O. ABRAMSKY, V. BARAK, N. CONFORTI, D. SAPHIER, AND J. WEIDENFELD. Effect of interleukin-1 on adreno- pra APS-Phys Rev Downloaded from on April 23, 2014 591. ANDREW V. TURNBULL AND CATHERINE L. RIVIER January 1999 620. 621. 622. 623. 624. 625. 626. 627. 629. 630. 631. 632. 633. 634. 635. 636. 637. 638. 639. cortical activity in intact and hypothalamic deafferented rats. Exp. Brain Res. 76: 246–249, 1989. PAAJANEN, H., W. GRODD, D. REVEL, B. ENGELSTAD, AND R. C. BRASCH. Gadolium-DTPA enhanced MR imaging of intramuscular abscesses. Magn. Reson. Imaging 5: 109–115, 1987. PANERI, A. E., AND P. SACERDOTE. b-Endorphin in the immune system: a role at last? Immunol. Today 18: 317–319, 1997. PAPANICOLAOU, D. A., J. S. PETRIDES, C. TSIGOS, S. BINA, K. T. KALOGERAS, R. WILDER, P. W. GOLD, P. A. DEUTSER, AND G. P. CHROUSOS. Exercise stimulates interleukin-6 secretion: inhibition by glucocorticoids and correlation with catecholamines. Am. J. Physiol. 271 (Endocrinol. Metab. 40): E601–E625, 1996. PARDY, K., D. MURPHY, D. CARTER, AND K. M. HUI. The influence of interleukin-2 on vasopressin and oxytocin gene expression in the rodent hypothalamus. J. Neuroimmunol. 42: 131–138, 1993. PARK, J. H., AND S. H. SHIN. Induction of interleukin-12 gene expression in the brain in septic shock. Biochem. Biophys. Res. Commun. 224: 391–396, 1996. PARNET, P., S. AMINDARI, C. WU, D. BRUNKE-REESE, E. GOUJON, J. A. WEYHENMEYER, R. DANTZER, AND K. W. KELLEY. Expression of type I and type II interleukin-1 receptors in mouse brain. Brain Res. 27: 63–70, 1994. PARNET, P., D. BRUNKE, E. GOUJON, J. DESMOTTES-MAINARD, A. BIRAGYN, S. ARKINS, R. DANTZER, AND K. W. KELLEY. Molecular identification of two types of IL-1 receptors in the murine pituitary gland. J. Neuroendocrinol. 5: 213–218, 1993. PARNET, P., K. E. GARKA, T. P. BONNERT, S. K. DOWER, AND J. E. SIMS. IL-1Rrp is a novel receptor-like molecule similar to the type I interleukin-1 receptor and its homolgues T1/ST2 and IL-1R AcP. J. Biol. Chem. 271: 3967–3970, 1996. PARSADAIANTZ, S. M., N. LEVIN, V. LENOIR, J. L. ROBERTS, AND B. KERDELHUE. Human interleukin-1b: corticotropin releasing factor and ACTH release and gene expression in the male rat: in vivo and in vitro studies. J. Neurosci. Res. 37: 675–682, 1994. PARSADANIANTZ, S. M., V. LENOIR, B. TERLAIN, AND B. KERDELHUE. Lack of effect of interleukins 1a and 1b, during in vitro perifusion, on anterior pituitary release of adrenocorticotropic hormone and b endorphin in the male rat. J. Neurosci. Res. 34: 315–323, 1993. PATH, G., AND S. R. BORNSTEIN. Interleukin-6 and interleukin-6 receptor in the human adrenal gland: expression and effects on steroidogenesis. J. Clin. Endocrinol. Metab. 82: 2343–2349, 1997. PATTERSON, J. C., AND G. V. CHILDS. Nerve growth factor and its receptor in the anterior pituitary. Endocrinology 135: 1689– 1696, 1994. PATTERSON, J. C., AND G. V. CHILDS. Nerve growth factor in the anterior pituitary: regulation of secretion. Endocrinology 135: 1697–1704, 1994. PAUL, W. E. Pleiotropy and redundancy: T-cell derived lymphokines in the immune response. Cell 57: 521–524, 1989. PAYNE, L. C., F. OBAL, M. R. OPP, AND J. M. KRUEGER. Stimulation and inhibition of growth hormone secretion by interleukin1b: the involvement of growth hormone-releasing hormone. Neuroendocrinology 56: 118–123, 1992. PAYNE, L. C., D. A. WEIGENT, AND J. E. BLALOCK. Induction of pituitary sensitivity to interleukin-1: a new function for corticotropin-releasing hormone. Biochem. Biophys. Res. Commun. 198: 480–484, 1994. PEQUEGNAT, W., N. A. GARRICK, AND E. STOVER. Neuroscience findings in AIDS: a review of research sponsored by the National Institute of Mental Health. Prog. Neuropsychopharmacol. Biol. Psychiatry 16: 145–170, 1992. PEREDA, M. P., V. GOLDBERG, A. CHERVIN, G. CARRIZO, A. MOLINA, J. ANDRADA, J. SAUER, U. RENNER, G. K. STALLA, AND E. ARZT. Interleukin-2 (IL-2) and IL-6 regulate c-fos protooncogene expression in human pituitary adenoma explants. Mol. Cell. Endocrinol. 124: 33–42, 1996. PERLSTEIN, R. S., N. R. MEHTA, E. H. MOUGEY, R. NETA, AND M. H. WHITNALL. Systemically administered H1 and H2 receptor antagonists do not block the ACTH response to bacterial lipopolysaccharide and interleukin-1. Neuroendocrinology 60: 418–425, 1994. PERLSTEIN, R. S., E. H. MOUGEY, W. E. JACKSON, AND R. NETA. / 9j0c$$oc11 P13-8 640. 641. 642. 643. 644. 645. 646. 647. 648. 649. 650. 651. 652. 653. 654. 655. 11-25-98 11:16:36 61 Interleukin-1 and interleukin-6 act synergistically to stimulate the release of adrenocorticotropic hormone in vivo. Lymphokine Cytokine Res. 10: 141–146, 1991. PERLSTEIN, R. S., M. H. WHITNALL, J. S. ABRAMS, E. H. MOUGHEY, AND R. NETA. Synergistic roles of interleukin-6, interleukin-1, and tumor necrosis factor in the adrenocorticotropin response to bacterial lipopolysaccharide in vivo. Endocrinology 132: 946–952, 1993. PETERS, M., S. JACOBS, M. EHLERS, P. VOLLMER, J. MULLBERG, E. WOLF, G. BREM, K.-H. MEYER ZUM BUSCHENFELDE, AND S. ROSE-JOHN. The function of the soluble interleukin-6 (IL6) receptor in vivo: sensitization of human soluble IL-6 receptor transgenic mice towards IL-6 and prolongation of the plasma halflife of IL-6. J. Exp. Med. 183: 1399–1406, 1996. PFEFFER, K., T. MATSUYAMA, T. M. KUNDIG, A. WAKEMAN, K. KISHIHARA, A. SHAHINIAN, K. WIEGMANN, P. S. OHASHI, M. KRONKE, AND T. W. MAK. Mice deficient for the 55 kD tumor necrosis factor receptor are resistant to endotoxic shock, yet succumb to L. monocytogenes infection. Cell 73: 7698–7702, 1993. PITOSSI, F. J., AND H. O. BESEDOVSKY. A multispecific internal control (pRat6) for the analysis of rat cytokine mRNA levels by quantitative RT-PCR. Eur. Cytokine Netw. 7: 377–379, 1996. PITOSSI, F., A. DEL REY, A. KABIERSCH, AND H. BESEDOVSKY. Induction of cytokine transcripts in the CNS and pituitary following peripheral administration of endotoxin to mice. J. Neurosci. Res. 48: 287–298, 1997. PITTERMAN, A. B., G. FIEDLANDER, G. KELLY, T. G. ROPCHACK, D. J. GOLDSTEIN, AND H. R. KEISER. Abdominal vagotomy does not modify endotoxic shock in rats. Life Sci. 33: 1033– 1037, 1983. PLATA-SALAMAN, C. R., AND S. E. ILYIN. Interleukin-1 beta (IL1 beta)-induced modulation of the hypothalamic IL-1 beta system, tumor necrosis factor-alpha, and transforming growth factor beta 1 mRNAs in obese (fa/fa) and lean (Fa/Fa) Zucker rats: implications to IL-1 beta feedback systems and cytokine-cytokine interactions. J. Neurosci. Res. 49: 541–550, 1997. PLOTKIN, S. R., W. A. BANKS, AND A. J. KASTIN. Comparison of saturable transport and extracellular pathways in the passage of interleukin-1b across the blood-brain barrier. J. Neuroimmunol. 67: 41–47, 1996. PLOTSKY, P. M. Pathways to the secretion of adrenocorticotropin: a view from the portal. J. Neuroendocrinol. 3: 1–9, 1991. PLOTSKY, P. M., E. T. J. CUNNINGHAM, AND E. P. WIDMAIER. Catecholaminergic modulation of corticotropin-releasing factor and adrenocorticotropin secretion. Endocr. Rev. 10: 437–458, 1989. PLOTSKY, P. M., A. KJAER, S. W. SUTTON, P. E. SAWCHENKO, AND W. VALE. Central activin administration modulates corticotropin-releasing hormone and adrenocorticotropin secretion. Endocrinology 128: 2520–2525, 1991. PLOTSKY, P. M., AND P. E. SAWCHENKO. Hypophysial portal plasma levels, median eminence content and immunohistochemical staining of corticotropin-releasing factor, arginine vasopressin and oxytocin following pharmacological adrenalectomy. Endocrinology 120: 1361–1369, 1987. POZZOLI, G., A. COSTA, M. GRIMALDI, G. SCHETTINI, P. PREZIOSI, A. GROSSMAN, AND P. NAVARRA. Lipopolysaccharide modulation of eicosanoid and corticotropin-releasing hormone release from rat hypothalamic explants and astrocyte cultures in vitro: evidence for the involvement of prostaglandin E2 but not prostaglandin F2 alpha and lack of effect of nerve growth factor. J. Endocrinol. 140: 103–109, 1994. POZZOLI, G., C. MANCUSO, A. MIRTELLA, P. PREZIOSI, A. B. GROSSMAN, AND P. NAVARRA. Carbon monoxide as a novel neuroendocrine modulator: inhibition of stimulated corticotropin-releasing hormone release from acute rat hypothalamic explants. Endocrinology 135: 2314–2317, 1994. PURBA, J. S., F. C. RAADSHEER, M. A. HOFMAN, R. RAVID, C. H. POLMAN, W. KAMPHORST, AND D. F. SWAAB. Increased number of corticotropin-releasing hormone expressing neurons in the hypothalamic paraventricular nucleus of patients with multiple sclerosis. Neuroendocrinology 62: 62–70, 1995. QUAN, N., S. K. SUNDAR, AND J. M. WEISS. Induction of interleu- pra APS-Phys Rev Downloaded from on April 23, 2014 628. REGULATION OF HPA AXIS BY CYTOKINES 62 656. 657. 658. 659. 660. 661. 662. 664. 665. 666. 667. 668. 669. 670. 671. 672. 673. 674. kin-1 in various brain regions after peripheral and central injections of lipopolysaccharide. J. Neuroimmunol. 49: 125–134, 1994. QUAN, N., Z. ZHANG, M. EMERY, R. BONSALL, AND J. M. WEISS. Detection of interleukin-1 bioactivity in various brain regions of normal healthy rats. Neuroimmunomodulation 3: 47–55, 1996. QUAN, N., Z. ZHANG, M. EMERY, E. LAI, R. BONSALL, V. S. KALYANARAMAN, AND J. M. WEISS. In vivo induction of interleukin-1 bioactivity in brain tissue after intracerebral infusion of native gp120 and gp160. Neuroimmunomodulation 3: 56–61, 1996. RABER, J., AND F. E. BLOOM. IL-2 induces vasopressin release from the hypothalamus and the amygdala: role of nitric oxidemediating signal. J. Neurosci. 14: 6187–6195, 1994. RABER, J., G. F. KOOB, AND F. E. BLOOM. Interleukin-2 (IL-2) induces corticotropin-releasing factor (CRF) release from the amygdala and involves a nitric oxide-mediated signaling: comparison with the hypothalamic response. J. Pharmacol. Exp. Ther. 272: 815–824, 1995. RABER, J., G. F. KOOB, AND F. E. BLOOM. Interferon-g and transforming growth factor-b1 regulate corticotropin-releasing factor release from the amygdala: comparison with the hypothalamic response. Neurochem. Int. 30: 455–463, 1997. RABER, J., S. M. TOGGAS, S. LEE, F. E. BLOOM, C. J. EPSTEIN, AND L. MUCKE. Central nervous system expression of HIV-1 Gp120 activates the hypothalamic-pituitary-adrenal axis: evidence for involvement of NMDA receptors and nitric oxide synthase. Virology 226: 362–373, 1996. RADY, P. L., E. M. SMITH, P. CADET, M. R. OPP, S. K. TYRING, AND T. K. HUGHES. Presence of interleukin-10 transcripts in human pituitary and hypothalamus. Cell. Mol. Neurobiol. 15: 289– 296, 1995. RAIVICH, G., J. GEHRMANN, AND G. W. KREUTZBERG. Increase of macrophage colony-stimulating factor and granulocyte-macrophage colony-stimulating factor receptors in the regenerating rat facial nucleus. J. Neurosci. Res. 30: 682–686, 1991. RAPOPORT, S. I. Blood-Brain Barrier in Physiology and Medicine. New York: Raven, 1976. RASMUSSEN, A. K., U. FELDT-RASMUSSEN, AND K. BENDTZEN. The effect of interleukin-1 on the thyroid gland. Autoimmunity 16: 141–148, 1993. RAY, D., AND S. MELMED. Pituitary cytokine and growth factor expression and action. Endocr. Rev. 18: 206–228, 1997. RAY, D. W., S. G. REN, AND S. MELMED. Leukemia inhibitory factor (LIF) stimulates proopiomelanocortin (POMC) expression in a corticotroph cell line. Role of Stat pathway. J. Clin. Invest. 97: 1852–1859, 1996. REINISCH, N., M. WOLKERSDORFER, C. M. KAHLER, K. YE, C. A. DINARELLO, AND C. J. WIEDERMANN. Interleukin-1 receptor type I mRNA in mouse brain as affected by peripheral administration of bacterial lipopolysaccharide. Neurosci. Lett. 166: 165– 167, 1994. RENNER, U., C. J. NEWTON, U. PAGOTTO, J. SAUER, E. ARZT, AND G. STALLA. Involvement of interleukin-1 and interleukin-1 receptor antagonist in rat anterior pituitary cell growth regulation. Endocrinology 136: 3186–3193, 1995. RENNERT, P. D., AND G. HEINRICH. Nerve growth factor mRNA in brain: localization by in situ hybridization. Biochem. Biophys. Res. Commun. 138: 813–818, 1986. RETTORI, V., N. BELOVA, M. GIMENO, AND S. M. MCCANN. Inhibition of nitric oxide synthase in the hypothalamus blocks the increase in plasma prolactin induced by intraventricular injection of interleukin-1b in the rat. Neuroimmunomodulation 1: 116– 120, 1994. RETTORI, V., W. L. DEES, J. K. HINEY, K. LYSON, AND S. M. MCCANN. An interleukin-1-alpha-like neuronal system in the preoptic-hypothalamic region and its induction by bacterial lipopolysaccharide in concentrations which alter pituitary hormone release. Neuroimmunomodulation 1: 251–258, 1994. RETTORI, V., L. MILENKOVIC, B. A. BEUTLER, AND S. M. MCCANN. Hypothalamic action of cachectin to alter pituitary hormone release. Brain Res. Bull. 23: 471–475, 1989. REYES, T. M., AND C. L. COE. Interleukin-1b differentially affects interleukin-6 and soluble interleukin-6 receptor in the blood and / 9j0c$$oc11 P13-8 675. 676. 677. 678. 679. 680. 681. 682. 683. 684. 685. 686. 687. 688. 689. 690. 691. 692. 693. 694. 11-25-98 11:16:36 Volume 79 central nervous system of the monkey. J. Neuroimmunol. 66: 135–141, 1996. REZAI, A. R., A. REZAI, O. MARTINEZ-MAZA, M. VANDERMEYDEN, AND M. H. WEISS. Interleukin-6 and interleukin-6 receptor gene expression in pituitary tumors. J. Neuro-oncol. 19: 131– 135, 1994. RITCHIE, P. K., H. H. KNOGHT, M. ASHBY, AND A. M. JUDD. Serotonin increases interleukin-6 release and decreases tumor necrosis factor release from rat adrenal zona glomerulosa cells in vitro. Endocrine 5: 291–297, 1996. RITCHIE, P. K., B. L. SPANGELO, D. K. KRZYMOWSKI, T. B. ROSSITER, E. KURTH, AND A. M. JUDD. Adenosine increases interleukin 6 release and decreases tumor necrosis factor release from rat adrenal zona glomerulosa cells, ovarian cells, and peritoneal macrophages. Cytokine 9: 187–198, 1997. RIVEST, S. Molecular mechanism and neural pathways mediating the influence of interleukin-1 on the activity of neuroendocrine CRF motoneurons in the rat. Int. J. Dev. Neurosci. 13: 135–146, 1995. RIVEST, S., AND N. LAFLAMME. Neuronal activity and neuropeptide gene expression transcription in the brains of immune-challenged rats. J. Neuroendocrinol. 7: 501–525, 1995. RIVEST, S., N. LAFLAMME, AND R. E. NAPPI. Immune challenge and immobilization stress induce transcription of the gene encoding the CRF receptor in selective nuclei of the rat hypothalamus. J. Neurosci. 15: 2680–2695, 1995. RIVEST, S., AND C. RIVIER. Influence of the paraventricular nucleus of the hypothalamus in the alteration of neuroendocrine functions induced by intermittent footshock or interleukin. Endocrinology 129: 2049–2057, 1991. RIVEST, S., AND C. RIVIER. Stress and interleukin-1b-induced activation of c-fos, NGFI-B and CRF gene expression in the hypothalamic PVN: comparison between Sprague-Dawley, Fisher-344 and Lewis rats. J. Neuroendocrinol. 6: 101–117, 1994. RIVEST, S., AND C. RIVIER. The role of corticotropin-releasing factor and interleukin-1 in the regulation of neurons controlling reproductive functions. Endocr. Rev. 16: 177–199, 1995. RIVEST, S., G. TORRES, AND C. RIVIER. Differential effects of central and peripheral injection of interleukin-1b on brain c-fos expression and neuroendocrine functions. Brain Res. 587: 13–23, 1992. RIVIER, C. Effect of peripheral and central cytokines on the hypothalamo-pituitary-adrenal axis of the rat. Ann. NY Acad. Sci. 697: 97–105, 1993. RIVIER, C. Stimulatory effect of interleukin-1 beta on the hypothalamic-pitutary-adrenal axis of the rat: influence of age, gender and circulating sex steroids. J. Endocrinol. 140: 365–372, 1994. RIVIER, C. Blockade of nitric oxide formation augments ACTH released by blood-borne interleukin-1b: role of vasopressin, prostaglandins and a-1 adrenergic receptors. Endocrinology 136: 3597–3603, 1995. RIVIER, C. Influence of immune signals on the hypothalamic-pituitary axis of the rodent. Front. Neuroendocrinol. 16: 151–182, 1995. RIVIER, C. Mechanisms of altered prolactin secretion due to the administration of interleukin-1b into the brain ventricles of the rat. Neuroendocrinology 62: 198–206, 1995. RIVIER, C., R. CHIZZONITE, AND W. VALE. In the mouse, the activation of the hypothalamic-pituitary-adrenal axis by a lipopolysaccharide (endotoxin) is mediated through interleukin-1. Endocrinology 125: 2800–2805, 1989. RIVIER, C., AND P. M. PLOTSKY. Mediation by corticotropin-releasing factor (CRF) of adenohypophysial hormone secretion. Annu. Rev. Physiol. 48: 475–494, 1986. RIVIER, C., AND G. H. SHEN. In the rat, endogenous nitric oxide modulates the response of the hypothalamo-pituitary-adrenal axis to interleukin-1b, vasopressin, and oxytocin. J. Neurosci. 14: 1985–1993, 1994. RIVIER, C., AND W. VALE. Interaction of corticotropin-releasing factor (CRF) and arginine vasopressin (AVP) on ACTH secretion in vivo. Endocrinology 113: 939–942, 1983. RIVIER, C., AND W. VALE. Stimulatory effect of interleukin-1 on pra APS-Phys Rev Downloaded from on April 23, 2014 663. ANDREW V. TURNBULL AND CATHERINE L. RIVIER January 1999 695. 696. 697. 698. 699. 700. 701. 702. 704. 705. 706. 707. 708. 709. 710. 711. 712. 713. 714. ACTH secretion in the rat: is it modulated by prostaglandins? Endocrinology 129: 384–388, 1991. RIVIER, C., W. VALE, AND M. BROWN. In the rat, interleukin-1a and -b stimulate adrenocorticotropin and catecholamine release. Endocrinology 125: 3090–3102, 1989. RIVIER, J., A. V. TURNBULL, AND C. RIVIER. Acute local inflammation induces temporally distinct patterns of c-fos expression in the rat brain (Abstract). Proc. Annu. Meet. Soc. Neurosci. 27th New Orleans LA 1997 p. 593-2. ROBERTS, V. J., S. L. BARTH, H. MEUNIER, AND W. VALE. Hybridization histochemical and immunohistochemical localization of inhibin/activin subunits and messenger ribonucleic acids in the rat brain. J. Comp. Neurol. 364: 473–493, 1996. ROH, M. S., K. A. DRAZENOVICH, J. J. BARBOSE, C. A. DINARELLO, AND C. F. COBB. Direct stimulation of the adrenal cortex by interleukin-1. Surgery 102: 140–146, 1987. ROMANOVSKY, A. A., V. A. KULCHITSKY, C. T. SIMONS, N. SUGIMOTO, AND M. SZEKELY. Febrile responsiveness of vagotomized rats is suppressed even in the absence of malnutrition. Am. J. Physiol. 273 (Regulatory Integrative Comp. Physiol. 42): R777– R783, 1997. ROMANOVSKY, A. A., V. A. KULCHITSKY, C. T. SIMONS, N. SUGIMOTO, AND M. SZEKELY. Cold defense mechanisms in vagotomized rats. Am. J. Physiol. 273 (Regulatory Integrative Comp. Physiol. 42): R784–R789, 1997. ROMANOVSKY, A. A., C. T. SIMONS, M. SZEKELY, AND V. A. KULCHITSKY. The vagus nerve in the thermoregulatory response to systemic inflammation. Am. J. Physiol. 273 (Regulatory Integrative Comp. Physiol. 42): R407–R413, 1997. ROOSTH, J., R. B. POLLARD, S. L. BROWN, AND W. J. MEYER. Cortisol stimulation by recombinant interferon-a2. J. Neuroimmunol. 12: 311–316, 1986. ROSE-JOHN, S., AND P. C. HEINRICH. Soluble receptors for cytokines and growth factors: generation and biological function. Biochem. J. 300: 281–290, 1994. ROTEIN, P., S. K. BURGESS, J. D. MILDBRANDT, AND J. E. KRAUSE. Differential expression of insulin-like growth factor genes in rat central nervous system. Proc. Natl. Acad. Sci. USA 85: 265–269, 1988. ROTH, J., C. A. CONN, M. J. KLUGER, AND E. ZEISBERGER. Kinetics of systemic and intrahypothalamic IL-6 and tumor necrosis factor during endotoxin fever in guinea pigs. Am. J. Physiol. 265 (Regulatory Integrative Comp. Physiol. 34): R653–R658, 1993. ROTH, P., A. BARTOCCI, AND E. R. STANLEY. Lipopolysaccharide induces synthesis of mouse colony-stimulating factor-1 in vivo. J. Immunol. 158: 3874–3880, 1997. ROTHE, J., W. LESSLAUER, H. LOETSCHER, Y. LANG, P. LOEBEL, F. KOENTGEN, A. ALTHAGE, R. ZINKERNAGEL, M. STEINMETZ, AND H. BLUETHMANN. Mice lacking the tumor necrosis receptor 1 are resistant to TNF-mediated toxicity but highly susceptible to infection by Listeria monocytokgens. Nature 364: 798–802, 1993. ROTHWELL, N. J. Functions and mechanisms of interleukin-1 in the brain. Trends Pharmacol. Sci. 12: 430–436, 1991. ROTHWELL, N. J., N. J. BUSBRIDGE, H. HUMPHRAY, AND P. HISSEY. Central actions of interleukin-1b on fever and thermogenesis. In: The Physiological and Pathological Effects of Cytokines, edited by C. A. Dinarello, M. J. Kluger, J. J., Powanda, and J. J. Oppenheim. New York: Wiley-Liss, 1990, p. 307–311. ROTHWELL, N. J., AND S. J. HOPKINS. Cytokines and the central nervous system II: actions and mechanism of action. Trends Neurosci. 18: 130–136, 1995. ROTHWELL, N. J., G. LUHESHI, AND S. TOULMOND. Cytokines and their receptors in the central nervous system: physiology, pharmacology, and pathology. Pharmacol. Ther. 69: 85–95, 1996. ROTONDO, D., H. T. ABUL, A. S. MILTON, AND J. DAVIDSON. Pyrogenic immunomodulators increase the level of prostaglandin E2 in the blood simultaneously with the onset of fever. Eur. J. Pharmacol. 154: 145–152, 1988. ROTT, O., U. TONTSCH, B. FLEISCHER, AND E. CASH. Interleukin-6 production in ‘‘normal’’ and HTLV-1 tax-expressing brainspecific endothelial cells. Eur. J. Immunol. 23: 1987–1991, 1993. RUBIO, N. Demonstration of the presence of an interleukin-1 re- / 9j0c$$oc11 P13-8 715. 716. 717. 718. 719. 721. 722. 723. 724. 725. 726. 727. 728. 729. 730. 731. 732. 733. 734. 735. 736. 11-25-98 11:16:36 63 ceptor on the surface of murine astrocytes and its regulation by cytokines and Theilers virus. Immunology 82: 178–183, 1994. RUTANEN, E.-M. Cytokines in reproduction. Trends Mol. Med. 25: 343–347, 1993. RUZEK, M. C., A. H. MILLER, S. M. OPAL, B. D. PEARCE, AND C. A. BIRON. Characterization of early cytokine responses and an interleukin (IL)-6-dependent pathway of endogenous glucocorticoid induction during murine cytomegalovirus infection. J. Exp. Med. 185: 1185–1192, 1997. RUZICKA, B. B., AND H. AKIL. Differential cellular regulation of pro-opiomelanocortin by interleukin-1-beta and corticotropin-releasing hormone. Neuroendocrinology 61: 136–151, 1995. SAGAR, S. M., K. J. PRICE, N. W. KASTING, AND F. R. SHARP. Anatomic patterns of FOS immunostaining in rat brain following systemic endotoxin administration. Brain Res. Bull. 36: 381–392, 1995. SAIJA, A., P. PRINCI, M. LANZA, M. SCALESSE, E. ARAMNEJAD, AND A. DE SARRO. Systemic administration can affect blood-brain barrier permeability. Life Sci. 56: 775–784, 1995. SAKAMOTO, Y., K. KOIJE, H. KIYAMA, K. KONISHI, K. WATANABE, Y. OSAKO, K. HIROTA, AND A. MIYAKE. Endotoxin activates a chemokinergic neuronal pathway in the hypothalamo-pituitary system. Endocrinology 137: 4503–4506, 1996. SALAS, M. A., S. W. EVANS, M. J. LEVELL, AND J. T. WHICHER. Interleukin-6 and ACTH act synergistically to stimulate the release of corticosterone from adrenal gland cells. Clin. Exp. Immunol. 79: 470–473, 1990. SANDBERG, A. C., C. ENGBERG, M. LAKE, H. VON HOLST, AND V. R. SARA. The expression of insulin-like growth factor I and insulin-like growth factor II genes in the human fetal and adult brain and in glioma. Neurosci. Lett. 93: 114–119, 1988. SANDI, C., AND C. GUAZA. Evidence for a role of nitric oxide in the corticotropin-releasing factor release induced by interleukin1b. Eur. J. Pharmacol. 274: 17–23, 1995. SAPHIER, D. Neurophysiological and endocrine consequences of immune activity. Psychoneuroendocrinology 14: 63–87, 1989. SAPHIER, D. Neuroendocrine effects of interferon-alpha in the rat. Adv. Exp. Med. Biol. 373: 209–218, 1995. SAPHIER, D., AND S. FELDMAN. Adrenoceptor specificity in the central regulation of adrenocortical secretion. Neuropharmacology 28: 1231–1237, 1989. SAPHIER, D., AND H. OVADIA. Selective facilitation of putative corticotropin-releasing factor-secreting neurons by interleukin-1. Neurosci. Lett. 114: 283–288, 1990. SAPHIER, D., S. C. ROERIG, C. ITO, W. R. VLASAK, G. E. FARRAR, J. E. BROYLES, AND J. E. WELCH. Inhibition of neural and neuroendocrine activity by alpha-interferon: neuroendocrine, electrophysiological, and biochemical studies in the rat. Brain Behav. Immun. 8: 37–56, 1994. SAPOLSKY, R., C. RIVIER, G. YAMAMOTO, P. PLOTSKY, AND W. VALE. Interleukin-1 stimulates the secretion of hypothalamic corticotropin-releasing factor. Science 238: 522–524, 1987. SARKAR, D. K., K. H. KIM, AND S. MINAMI. Transforming growth factor-b1 messenger RNA and protein expression in the pituitary gland: its action on prolactin secretion and lactotropic growth. Mol. Endocrinol. 6: 1825–1833, 1992. SARLIS, N. J., A. STEPHANOU, R. A. KNIGHT, S. L. LIGHTMAN, AND H. S. CHOWDREY. Effects of glucocorticoids and chronic inflammatory stress upon anterior pituitary interleukin-6 mRNA in the rat. Br. J. Rheumatol. 32: 653–657, 1993. SATO, N., AND A. MIYAJIMA. Multimeric cytokine receptors: common versus specific functions. Curr. Opin. Cell Biol. 6: 174–179, 1994. SAUER, J., E. ARZT, H. GUMPRECHT, U. HOPFNER, AND G. K. STALLA. Expression of interleukin-1 receptor antagonist in human pituitary adenomas in vitro. J. Clin. Endocrinol. Metab. 79: 1857–1863, 1994. SAWADA, M., Y. ITOH, A. SUZUMURA, AND T. MARUNOUCHI. Expression of cytokine receptors in cultured neuronal and glial cell lines. Neurosci. Lett. 160: 131–134, 1993. SAWADA, M., A. SUZUMURA, Y. ITOH, AND T. MARUNOUCHI. Production of interleukin-5 by mouse astrocytes and microglia in culture. Neurosci. Lett. 155: 175–178, 1993. pra APS-Phys Rev Downloaded from on April 23, 2014 703. REGULATION OF HPA AXIS BY CYTOKINES 64 ANDREW V. TURNBULL AND CATHERINE L. RIVIER / 9j0c$$oc11 P13-8 755. 756. 757. 758. 759. 760. 761. 762. 763. 764. 765. 766. 767. 768. 769. 770. 771. 772. 773. 774. 11-25-98 11:16:36 receptor antagonist protein and mRNA in the rat adrenal gland. J. Interferon Cytokine Res. 15: 721–729, 1995. SCHWARTZ, G. J., C. R. PLATA-SALAMAN, AND W. LANGHANS. Subdiaphragmatic vagal deafferentation fails to block feeding suppressive effects of LPS and IL-1 beta in rats. Am. J. Physiol. 273 (Regulatory Integrative Comp. Physiol. 42): R1193–R1198, 1997. SCHWARTZ, J., AND D. W. RAY. Leukemia inhibitory factor as an intrapituitary mediator of ACTH secretion in normal sheep anterior pituitary. Proc. Annu. Meet. Endocr. Soc. 79th Minneapolis MN 1997, p. 2–161. SCHWEIGERER, L., G. NEUFELD, J. FRIEDMAN, J. A. ABRAHAM, J. C. FIDDES, AND D. GOSPODAROWICZ. Basic fibroblast growth factor: production and growth stimulation in cultured adrenal cortex cells. Endocrinology 120: 796–800, 1987. SCOTT, G. M., R. J. WARD, D. J. WRIGHT, J. A. ROBINSON, J. K. ONWUBALILI, AND C. L. GAUCI. Effects of cloned interferon a2 in normal volunteers: febrile reactions and changes in circulating corticosteroids and trace metals. Antimicrob. Agents Chemother. 23: 589–592, 1983. SEGRETI, J., G. GHEUSI, R. DANTZER, K. W. KELLEY, AND R. W. JOHNSON. Defect in interleukin-1beta secretion prevents sickness behavior in C3H/HeJ mice. Physiol. Behav. 61: 873–878, 1997. SEHGAL, P. B. Interleukin-6-type cytokines in vivo: regulated bioavailability. Proc. Soc. Exp. Biol. Med. 213: 238–247, 1996. SEHIC, E., AND C. M. BLATTEIS. Blockade of lipopolysaccharideinduced fever by subdiaphragmatic vagotomy in guinea pigs. Brain Res. 726: 160–166, 1996. SEI, Y., L. VITKOVIC, AND M. M. YOKOYAMA. Cytokines in the central nervous system: regulatory roles in neuronal function, cell death and repair. Neuroimmunomodulation 2: 121–133, 1995. SELLMEYER, D. E., AND C. GRUNFIELD. Endocrine and metabolic disturbances in human immunodeficiency virus infection and the acquired immune deficiency syndrome. Endocr. Rev. 17: 518– 532, 1996. SELYE, H. A syndrome produced by diverse nocuous agents. Nature 138: 32, 1936. SELYE, H. Thymus and adrenals in the response of the organism to injuries and intoxications. Br. J. Exp. Pathol. 17: 234–248, 1936. SHALABY, M. R., A. WAAGE, L. A. AARDEN, AND T. ESPEVICK. Endotoxin, tumor necrosis factor a and interleukin-1 induce interleukin-6 production in vivo. Clin. Immunol. Immunopathol. 53: 3131–3133, 1989. SHANKS, N., D. FRANCIS, S. ZALCMAN, M. J. MEANEY, AND H. ANISMAN. Alterations in central catecholamines associated with immune responding in adult and aged mice. Brain Res. 666: 77– 87, 1994. SHARIEF, M. K., M. CIARDI, AND E. J. THOMPSON. Blood-brain barrier damage in patients with bacterial meningitis: association with tumor necrosis factor-a but not interleukin-1b. J. Infect. Dis. 166: 350–358, 1992. SHARIEF, M. K., AND E. J. THOMPSON. In vivo relationship of tumor necrosis factor-a to blood-brain barrier damage in patients with active multiple sclerosis. J. Neuroimmunol. 38: 27–34, 1992. SHARIF, S. F., R. J. HAIRI, V. A. CHANG, P. S. BARIE, R. S. WANG, AND J. B. GHAJAR. Human astrocyte production of tumor necrosis factor-alpha, interleukin-1 beta, and interleukin-6 following exposure to lipopolysaccharide endotoxin. Neurol. Res. 15: 109–112, 1993. SHARP, B. M., AND S. G. MATTA. Prostaglandins mediate the adrenocorticotropin response to tumor necrosis factor in rats. Endocrinology 132: 269–274, 1993. SHARP, B. M., S. G. MATTA, P. K. PETERSON, R. NEWTON, C. CHAO, AND K. MCALLEN. Tumor necrosis factor-a is a potent ACTH secretagogue: comparison with interleukin-1b. Endocrinology 124: 3131–3133, 1989. SHIMIZU, H., Y. UEHARA, Y. SHIMOMURA, M. NEGISHI, S. TAKAHASHI, I. KOBAYASHI, AND S. KOBAYASHI. Effects of recombinant human interleukin-1 beta on hypothalamic monoamine metabolism of rats. Biogenic Amines 7: 517–523, 1990. SHIMON, I., D. W. RAY, AND S. MELMED. Cytokine-dependent gp130 receptor subunit regulates human fetal pituitary adrenocorticotropin hormone and growth hormone secretion. J. Clin. Invest. 100: 357–363, 1997. pra APS-Phys Rev Downloaded from on April 23, 2014 737. SAWADA, T., K. KOIKE, Y. KANDA, Y. SAKAMOTO, A. NOHARA, M. OHMICHI, K. HIROTA, AND A. MIYAKE. In vitro effects of cinc/ gro, a member of the interleukin-8 family, on hormone secretion by rat anterior pituitary cells. Biochem. Biophys. Res. Commun. 202: 155–160, 1994. 738. SAWCHENKO, P. E., E. R. BROWN, R. K. W. CHAN, A. ERICSSON, H.-Y. LI, B. L. ROLAND, AND K. J. KOVACS. The paraventricular nucleus of the hypothalamus and functional neuroanatomy of visceromotor responses to stress. Prog. Brain Res. 107: 201–222, 1996. 739. SAWCHENKO, P. E., E. T. J. CUNNINGHAM, J. C. BITTENCOURT, AND R. K. W. CHAN. Aminergic and peptidergic pathways subserving the stress response. In: Stress: Neuroendocrine and Molecular Approaches, edited by R. Kvetnansky, R. McCarty, and J. Axelrod. New York: Gordon & Breach, 1992, p. 15–27. 740. SAWCHENKO, P. E., L. W. SWANSON, AND W. W. VALE. Co-expression of CRF- and vasopressin-immunoreactivity in parvocellular neurosecretory neurons in the adrenalectomized rat. Proc. Natl. Acad. Sci. USA 81: 1883–1887, 1984. 741. SCACCIANOCE, S., G. CIGLIANA, R. NICOLAI, L. A. MUSCULO, A. PORCU, D. NAVARRA, J. R. PEREZ-POLO, AND L. ANGELUCCI. Hypothalamic involvement in the activation of the pituitary-adrenocortical axis by nerve growth factor. Neuroendocrinology 58: 202–209, 1993. 742. SCAMMELL, T. E., J. K. ELMQUIST, J. D. GRIFFIN, AND C. B. SAPER. Ventromedial preoptic prostaglandin E2 activates feverproducing autonomic pathways. J. Neurosci. 16: 6246–6254, 1996. 743. SCHINDLER, R., J. MANCILLA, S. ENDRES, R. GHORBANI, S. C. CLARK, AND C. A. DINARELLO. Correlations and interactions in the production of interleukin-6 (IL-6), IL-1, and tumor necrosis factor in human blood mononuclear cells: IL-6 supresses IL-1 and TNF. Blood 75: 40–47, 1990. 744. SCHMIDT, E. D., A. W. J. W. JANSZEN, F. G. WOUTERLOOD, AND F. J. H. TILDERS. Interleukin-1-induced long-lasting changes in hypothalamic corticotropin-releasing hormone (CRH)-neurons and hyperresponsiveness of the hypothalamus-pituitary-adrenal axis. J. Neurosci. 15: 7417–7426, 1995. 745. SCHOBITZ, B., E. R. DE KLOET, AND F. HOLSBOER. Gene expression and function of interleukin 1, interleukin 6 and tumor necrosis factor in the brain. Prog. Neurobiol. 44: 397–432, 1994. 746. SCHOBITZ, B., E. R. DE KLOET, W. SUTANTO, AND F. HOLSBOER. Cellular localization of interleukin-6 mRNA and interleukin-6 receptor mRNA in rat brain. Eur. J. Neurosci. 5: 1426–1435, 1993. 747. SCHOBITZ, B., G. PEZESHKI, T. POHL, U. HEMMANN, P. C. HEINRICH, F. HOLSBOER, AND M. H. M. REUL. Soluble interleukin6 (IL-6) receptor augments central effects of IL-6 in vivo. FASEB J. 9: 659–664, 1995. 748. SCHOBITZ, B., M. VAN DEN DOBBELSTEEN, F. HOLSBOER, W. SUTANTO, AND E. R. DE KLOET. Regulation of interleukin-6 gene expression in rat. Endocrinology 132: 1569–1576, 1993. 749. SCHOBITZ, B., D. A. M. VOORHUIS, AND E. R. DE KLOET. Localization of interleukin-6 mRNA and interleukin 6 receptor mRNA in rat brain. Neurosci. Lett. 136: 189–192, 1992. 750. SCHOTANUS, K., G. B. MAKARA, F. J. H. TILDERS, AND F. BERKENBOSCH. ACTH response to a low dose but not a high dose of bacterial endotoxin in rats is completely mediated by corticotropin-releasing hormone. Neuroimmunomodulation 1: 300–307, 1994. 751. SCHOTANUS, K., R. H. MELOEN, W. C. PUJIK, F. BERKENOBOSCH, R. BINNEKADE, AND F. J. H. TILDERS. Effects of monoclonal antibodies to specific epitopes of rat interleukin-1 beta (IL1b) on IL-1b-induced ACTH corticosterone and IL-6 responses in rats. J. Neuroendocrinol. 7: 255–262, 1995. 752. SCHOTANUS, K., F. J. TILDERS, AND F. BERKENBOSCH. Human recombinant interleukin-1 receptor antagonist prevents adrenocorticotropin, but not interleukin-6 responses to bacterial endotoxin. Endocrinology 133: 2461–2468, 1993. 753. SCHULTZBERG, M., C. ANDERSSON, A. UNDEN, M. TROYEBLOMBERG, S. B. SVENSON, AND T. BARTFAI. Interleukin-1 in adrenal chromaffin cells. Neuroscience 30: 805–810, 1989. 754. SCHULTZBERG, M., S. TINGSBORG, S. NOBEL, J. LUNDKVIST, S. SVENSON, A. SIMONCSITS, AND T. BARTFAI. Interleukin-1 Volume 79 January 1999 REGULATION OF HPA AXIS BY CYTOKINES / 9j0c$$oc11 P13-8 794. 795. 796. 797. 798. 799. 800. 801. 802. 803. 804. 805. 806. 807. 808. 809. 810. 811. 11-25-98 11:16:36 corticosterone in hypophysectomized mice: a possible lymphoid adrenal axis. Science 218: 1311–1312, 1982. SMITH, E. M., M. PHAN, T. E. KRUGER, D. H. COPPENHAVER, AND J. E. BLALOCK. Human lymphocyte production of immunoreactive thyrotropin. Proc. Natl. Acad. Sci. USA 80: 6010–6013, 1983. SMITH, J. W., W. J. URBA, B. D. CURTI, L. J. ELWOOD, R. G. STEIS, J. E. JANIK, W. H. SHARFMAN, L. L. MILLER, R. G. FENTON, K. C. CONLON, M. SZNOL, S. P. CREEKMORE, N. F. WELLS, F. W. RUSCETTI, J. R. KELLER, K. HESTDAL, M. SHIMUZU, J. ROSSIO, W. G. ALVORD, J. J. OPPENHEIM, AND D. L. LONGO. The toxic and hematologic effects of interleukin-1 alpha administered in a phase I trial to patients with advanced malignancies. J. Clin. Oncol. 10: 1141–1152, 1992. SMITH, L. R., S. L. BROWN, AND J. E. BLALOCK. Interleukin-2 induction of ACTH secretion: presence of an interleukin-2 receptor alpha-chain-like molecule on pituitary cells. J. Neuroimmunol. 21: 249–254, 1989. SMITH, M. A., S. MAKINO, S. Y. KIM, AND R. KVETNANSKY. Stress increases brain-derived neurotropic factor messenger ribonucleic acid in the hypothalamus and pituitary. Endocrinology 136: 3743– 3750, 1995. SMITH, M. A., S. MAKINO, R. KVETNANSKY, AND R. M. POST. Stress and glucocorticoids affect the expression of brain-derived neurotrophic and neurotrophin-3 mRNAs in the hippocampus. J. Neurosci. 15: 1768–1777, 1995. SMITH, T., A. K. HEWSON, L. QUARRIE, J. P. LEONARD, AND M. L. CUZNER. Hypothalamic PGE2 and cAMP production and adrenocortical activation following intraperitoneal endotoxin injection: in vivo microdialysis studies in Lewis and Fischer rats. Neuroendocrinology 59: 396–405, 1994. SOSZYNSKI, D., W. KOZAK, C. A. CONN, K. RUDOLPH, AND M. J. KLUGER. Beta-adrenoceptor antagonists suppress elevation in body temperature and increase in plasma IL-6 in rats exposed to open field. Neuroendocrinology 63: 459–467, 1996. SPANGELO, B. L., P. D. DEHOLL, L. KALABAY, B. R. BOND, AND P. ARNAUD. Neurointermediate pituitary lobe cells synthesize and release interleukin-6 in vitro: effects of lipopolysaccharide and interleukin-1b. Endocrinology 135: 556–563, 1994. SPANGELO, B. L., AND W. C. GOROSPE. Role of cytokines in the neuroendocrine-immune system axis. Front. Neuroendocrinol. 16: 1–22, 1995. SPANGELO, B. L., P. C. ISAKSON, AND R. M. MACLEOD. Production of interleukin-6 by anterior pituitary cells is stimulated by increased intracellular adenosine 3*,5*-monophosphate and vasoactive intestinal peptide. Endocrinology 127: 2886–2894, 1990. SPANGELO, B. L., AND W. D. JARVIS. Lysophosphatidylcholine stimulates interleukin-6 release from rat anterior pituitary cells in vitro. Endocrinology 137: 4419–4426, 1996. SPANGELO, B. L., W. D. JARVIS, A. M. JUDD, AND R. M. MACLEOD. Induction of interleukin-6 release by interleukin-1 in rat anterior pituitary cells in vitro: evidence for an eicosanoid-dependent mechanism. Endocrinology 129: 2886–2894, 1991. SPANGELO, B. L., A. M. JUDD, P. C. ISAKSON, AND R. M. MACLEOD. Interleukin-1 stimulates interleukin-6 release from rat anterior pitutary cells in vitro. Endocrinology 128: 2685–2692, 1991. SPANGELO, B. L., R. M. MACLEOD, AND P. C. ISAKSON. Production of interleukin-6 by anterior pituitary cells in vitro. Endocrinology 126: 582–586, 1990. SPANGELO, B. L., AND R. M. WRIGHT. Arachidonic acid stimulates interleukin-6 release from rat anterior pituitary cells in vitro: comparison with peritoneal macrophages. Prog. Neuroendocrinol. Immunol. 5: 235–243, 1992. SPATH-SCHWALBE, E., J. BORN, H. SCHREZENMEIER, S. R. BORNSTEIN, P. STROMEYER, S. DRESCHSLER, AND H.-L. FEHM. Interleukin-6 stimulates the hypothalamo-pituitary-adrenocortical axis in man. J. Clin. Endocrinol. Metab. 79: 1212–1214, 1994. SPATH-SCWALBE, E., F. PORZOLT, W. DIGEL, J. BORN, B. KLOSS, AND H. L. FEHM. Elevated plasma cortisol levels during interferon-gamma treatment. Immunopharmacology 17: 141–145, 1989. SPILLANTINI, M. G., L. ALOE, E. ALLEVA, R. DE SIMONE, M. GOEDERT, AND R. LEVI-MONTALCINI. Nerve growth factor pra APS-Phys Rev Downloaded from on April 23, 2014 775. SHIMON, I., X. YAN, D. W. RAY, AND S. MELMED. Human fetal pituitary cells express functional gp130-related cytokine-specific receptors: regulation of ACTH and growth hormone secretion. Proc. Annu. Meet. Endocr. Soc. 79th Minneapolis MN 1997, p. OR42–5. 776. SHINTANI, F., S. KANBA, T. NAKAKI, M. NIBUYA, N. KINOSHITA, E. SUZUKI, G. YAGI, R. KATO, AND M. ASAI. Interleukin-1b augments release of norepinephrine, dopamine, and serotonin in the rat anterior hypothalamus. J. Neurosci. 13: 3574–3581, 1993. 777. SHINTANI, F., T. NAKAI, S. KANBA, R. KATO, AND M. ASAI. Role of interleukin-1 in stress responses. A putative neurotransmitter. Mol. Neurobiol. 10: 47–71, 1995. 778. SHINTANI, F., T. NAKAI, S. KANBA, S. KOICHI, G. YAGI, M. SHIOZAWA, S. ALSO, R. KATO, AND M. ASAI. Involvement of interleukin-1 in immobilization stress-induced increase in plasma adrenocorticotropic hormone and in release of hypothalamic catecholamines in the rat. J. Neurosci. 15: 1961–1970, 1995. 779. SHIZUYA, K., T. KOMORI, R. FUJIWARA, S. MIYAHARA, M. OHMORI, AND J. NOMURA. The influence of restraint stress on the exposure of mRNAs for IL-6 and the IL-6 receptor in the hypothalamus and midbrain of the rat. Life Sci. 61: 135–140, 1997. 780. SHOHAMI, E., R. BASS, D. WALLACH, A. YAMIN, AND R. GALLILY. Inhibition of tumor necrosis factor alpha (TNFa) activity in rat brain is associated with cerebroprotection after closed head injury. J. Cereb. Blood Flow Metab. 16: 378–384, 1996. 781. SHUKLA, A., M. DIKSHIT, AND R. C. SRIMAL. Nitric oxide modulates blood-brain barrier permeability during infections with an activated bacterium. Neuroreport 6: 1629–1632, 1995. 782. SIAUD, P., M. MEKAOUCHE, G. IXART, M. BALMEFREZOL, L. GIVALOIS, G. BARBANEL, AND I. ASSENMACHER. A subpopulation of corticotropin-releasing hormone neurosecretory cells in the paraventricular nucleus of the hypothalamus also contain NADPH-diaphorase. Neurosci. Lett. 170: 51–54, 1994. 783. SILVERMAN, A. J., D. L. HOFFMAN, AND E. A. ZIMMERMAN. The descending afferent connections of the paraventricular nucleus of the hypothalamus (PVN). Brain Res. Bull. 6: 47–61, 1981. 784. SIMS, J. E., AND S. K. DOWER. Interleukin-1 receptors. Eur. Cytokine Netw. 5: 539–546, 1994. 785. SIMS, J. E., M. A. GAYLE, J. L. SLACK, M. R. ALDERSON, T. A. BIRD, J. G. GIRI, F. COLOTTA, F. RE, A. MANTOVANI, K. SHANEBECK, K. H. GRABSTEIN, AND S. K. DOWER. Interleukin-1 signaling occurs exclusively via the type I receptor. Proc. Natl. Acad. Sci. USA 90: 6155–6159, 1993. 786. SIMS, J. E., J. G. GIRI, AND S. K. DOWER. The two interleukin1 receptors play different roles in IL-1 actions. Clin. Immunol. Immunopathol. 72: 9–14, 1994. 787. SIPE, K. J., D. SRISAWASDI, R. DANTZER, K. W. KELLEY, AND J. A. WEYHENMEYER. An endogenous 55 kDa TNF receptor mediates cell death in a neural cell line. Brain Res. 38: 222–232, 1996. 788. SIPPY, B. D., F. M. HOFMAN, D. WALLACH, AND D. R. HINTON. Increased expression of tumor necrosis factor-a receptors in the brains of patients with AIDS. J. Acquired Immune Deficiency Syndrome Hum. Retrovirol. 10: 511–521, 1995. 789. SIRKO, S., I. BISHAI, AND F. COCEANI. Prostaglandin formation in the hypothalamus in vivo: effect of pyrogens. Am. J. Physiol. 263 (Regulatory Integrative Comp. Physiol. 32): R616–R624, 1989. 790. SMAGIN, G. N., A. H. SWIERGIEL, AND A. J. DUNN. Peripheral administration of interleukin-1 increases extracellular concentrations of norepinephrine in rat hypothalamus: comparison with plasma corticosterone. Psychoneuroendocrinology 21: 83–93, 1996. 791. SMITH, B. K., AND M. J. KLUGER. Human IL-1 receptor antagonist partially suppresses LPS fever but not plasma levels of IL-6 in Fisher rats. Am. J. Physiol. 263 (Regulatory Integrative Comp. Physiol. 32): R653–R655, 1992. 792. SMITH, E. M., AND J. E. BLALOCK. Human lymphocyte production of corticotropin and endorphin-like substances: association with leukocyte interferon. Proc. Natl. Acad. Sci. USA 78: 7530–7534, 1981. 793. SMITH, E. M., W. J. MEYER, AND J. E. BLALOCK. Virus-induced 65 66 ANDREW V. TURNBULL AND CATHERINE L. RIVIER / 9j0c$$oc11 P13-8 828. SUZUKI, E., F. SHINTANI, S. KANBA, M. ASAI, AND T. NAKAKI. Immobilization stress increases levels of interleukin-1 receptor antagonist in various rat brain regions. Cell. Mol. Neurobiol. 17: 557–562, 1997. 829. SVANES, K. Diphasic increase in vascular permeability in turpentine induced inflammation in skin and musculature of mice. Acta Pathol. Microbiol. Scand. A79: 335–344, 1971. 830. SWEEP, C. G. J. F., M. J. M. VAN DER MEER, A. R. M. M. HERMUS, A. G. H. SMALS, J. W. M. VAN DER MEER, G. J. PESMAN, S. J. WILLEMSEN, T. J. BENRAAD, AND P. W. C. KLOPPENBORG. Chronic stimulation of the pituitary-adrenal axis in rats by interleukin-1b infusion: in vivo and in vitro studies. Endocrinology 130: 1153–1164, 1992. 831. SWIERGIEL, A. H., A. J. DUNN, AND E. A. STONE. The role of cerebral noradrenergic systems in the fos response to interleukin1. Brain Res. Bull. 41: 61–64, 1996. 832. SZAFARCZYK, A., G. ALONSO, G. IXART, F. MALAVAL, AND I. ASSENMACHER. Diurnal-stimulated and stress induced ACTH release is mediated by ventral noradrenergic bundle. Am. J. Physiol. 249 (Endocrinol. Metab. 12): E219–E226, 1985. 833. SZAFARCZYK, A., V. GUILLAUME, B. CONTE-DEVOLX, G. ALONSO, F. MALAVAL, N. PARES-HERBUTE, C. OLIVER, AND I. ASSENMACHER. Central catecholaminergic system stimulates secretion of CRH at different sites. Am. J. Physiol. 255 (Endocrinol. Metab. 18): E463–E468, 1988. 834. TADA, M., A.-C. DISERENS, I. DESBAILLETS, AND N. DE TRIBOLET. Analysis of cytokine receptor messenger RNA expression in human glioblastoma cells and normal astrocytes by reverse transcription polymerase chain reaction. J. Neurosurg. 80: 1063– 1073, 1994. 835. TAGA, T., K. KAWANISHI, R. R. HARDY, T. HIRANO, AND T. KISHIMOTO. Receptors for B cell stimulatory factor. 2. Quantification, specificity, distribution and regulation of their expression. J. Exp. Med. 166: 967–981, 1987. 836. TAGLIALATELA, G., L. ANGELUCCI, S. SCACCIANOCE, P. J. FOREMAN, AND J. R. PEREZ-POLO. Nerve growth factor modulates the activation of the hypothalamo-pituitary-adrenocortical axis during the stress response. Endocrinology 129: 2212–2218, 1991. 837. TAGOH, H., H. NISHIJO, T. UWANO, H. KISHI, T. ONO, AND A. MURAGUCHI. Reciprocal IL-1b gene expression in medial and lateral hypothalamic areas in SART-stressed mice. Neurosci. Lett. 184: 17–20, 1995. 838. TAISHI, P., S. BREDOW, N. GUHA-THAKURTA, F. O. OBAL, AND J. M. KRUEGER. Diurnal variations of interleukin-1b mRNA and b-actin mRNA in rat brain. J. Neuroimmunol. 75: 69–74, 1997. 839. TAKAHASHI, S., L. KAPAS, J. FANG, AND J. M. KRUEGER. An anti-tumor necrosis factor antibody suppresses sleep in rats and rabbits. Brain Res. 690: 241–244, 1995. 840. TAKAO, T., S. G. CULP, AND E. B. DE SOUZA. Reciprocal modulation of interleukin-1b (IL-1b) and IL-1 receptors by lipopolysaccharide (endotoxin) treatment in the mouse brain-endocrine-immune axis. Endocrinology 132: 1497–1504, 1993. 841. TAKAO, T., S. G. CULP, R. C. NEWTON, AND E. B. DE SOUZA. Type I interleukin-1 receptors in the mouse brain-endocrine-immune axis labeled with [125I]recombinant human interleukin-1 receptor antagonist. J. Neuroimmunol. 41: 51–60, 1992. 842. TAKAO, T., W. M. MITCHEL, AND E. B. DE SOUZA. Interleukin-1 receptors in mouse kidney: identification, localization, and modulation by lipopolysaccharide treatment. Endocrinology 128: 2618– 2624, 1991. 843. TAKAO, T., H. NAKATA, C. TOJO, H. KUROKAWA, T. NISHIOKA, K. HASHIMOTO, AND E. B. DE SOUZA. Regulation of interleukin1 receptors and hypothalamic-pituitary-adrenal axis by lipopolysaccharide treatment in the mouse. Brain Res. 649: 265–270, 1994. 844. TAKAO, T., W. NANAMIYA, T. TAKEMURE, M. NISHIYAMA, K. ASABA, S. MAKINO, K. HASHIMOTO, AND E. B. DE SOUZA. Endotoxin induced increases in rat plasma pituitary-adrenocortical hormones are better reflected by alterations in tumor necrosis factora than interleukin-1b. Life Sci. 61: 263–268, 1997. 845. TAKAO, T., R. C. NEWTON, AND E. B. DE SOUZA. Species differences [125I]interleukin-1 binding in brain, endocrine and immune tissues. Brain Res. 623: 172–176, 1993. 11-25-98 11:16:36 pra APS-Phys Rev Downloaded from on April 23, 2014 mRNA and protein increase in hypothalamus in a mouse model of aggression. Proc. Natl. Acad. Sci. USA 86: 8555–8559, 1989. 812. SPINAZZE, S., S. VIVIANI, P. BIDOLI, F. ROVELLI, P. PALMER, C. R. FRANKS, F. ARIENTI, L. RIVOLTINI, AND G. PARMIANI. Effect of prolonged subcutaneous administration of interleukin-2 on the circadian rhythms of cortisol and beta-endorphin in advanced small cell lung cancer patients. Tumor 77: 496–499, 1991. 813. SPINEDI, E., R. HADID, T. DANEVA, AND R. GAILLARD. Cytokines stimulate the CRH but not the vasopressin neuronal system: evidence for a median eminence site of interleukin-6 action. Neuroendocrinology 56: 46–53, 1992. 814. SPIVAK, B., B. SHOHAT, R. MESTER, S. AVRAHAM, I. GIL-AD, A. BLEICH, A. VALEVSKI, AND A. WEIZMAN. Elevated levels of serum interleukin-1 beta in combat related posttraumatic stress disorder. Biol. Psychiatry 42: 345–348, 1997. 815. SPRENGER, H., C. JACOBS, M. NAIN, A. M. GRESSNER, H. PRINZ, W. WESEMAN, AND S. GERNSA. Enhanced release of cytokines, interleukin-2 receptors, and neopterin after long-distance running. Clin. Immunol. Immunopathol. 63: 188–195, 1992. 816. STEFANA, B., D. W. RAY, AND S. MELMED. Leukemia inhibitory factor induces differentiation of pituitary corticotroph function: an immuno-neuroendocrine phenotypic switch. Proc. Natl. Acad. Sci. USA 93: 12502–12506, 1996. 817. STEFFERL, A., S. J. HOPKINS, N. J. ROTHWELL, AND G. N. LUHESHI. The role of TNF-a in fever: opposing actions of human and murine TNF-a and interactions with IL-1b in the rat. Br. J. Pharmacol. 118: 1919–1924, 1996. 818. STEPHANOU, A., N. J. SARLIS, R. A. KNIGHT, S. L. LIGHTMAN, AND H. S. CHOWDREY. Effects of cyclosporin A on the hypothalamo-pituitary-adrenal axis and anterior pituitary interleukin-6 mRNA expression during chronic inflammatory stress in the rat. J. Neuroimmunol. 41: 215–222, 1992. 819. STEPIEN, H., G. ZEREK-MEFEN, S. MUCHA, K. WINCZYK, AND J. FRYCZAK. Interleukin-1b stimulates cell proliferation in the intermediate lobe of the rat pituitary gland. J. Endocrinol. 140: 337–341, 1994. 820. STITT, J. T. Evidence for the involvement of the organum vasculosum laminae terminalis in the febrile response of rabbits and rats. J. Physiol. (Lond.) 368: 501–511, 1985. 821. STITT, J. T. Passage of immunomodulators across the blood-brain barrier. Yale J. Biol. Med. 63: 121–131, 1990. 822. STITT, J. T. Prostaglandin, the OVLT and fever. In: Neuroimmunology of Fever, edited by T. Bartfai and D. Ottoson. Oxford, UK: Pergamon, 1992, p. 155–165. 823. STOCKLI, K. A., L. E. LILLIEN, M. NAHER-NOE, G. BREITFELD, R. A. HUGHES, M. C. RAFF, H. THOENEN, AND M. SENDTNER. Regional distribution, developmental changes, and cellular localization of CNTF-mRNA and protein in the rat brain. J. Cell Biol. 115: 447–459, 1991. 823a. ST. PIERRE, B. A., D. A. GRANGER, J. L. WONG, AND J. E. MERRIL. A study of tumor necrosis factor, tumor necrosis factor receptors, and nitric oxide in human fetal glial cells. Adv. Pharmacol. 34: 415–438, 1995. 824. SUDA, T., F. TOZAWA, T. USHIYAMA, T. SUMITOMO, M. YAMADA, AND H. DEMURA. Interleukin-1 stimulates corticotropinreleasing factor gene expression in rat hypothalamus. Endocrinology 126: 1223–1228, 1990. 825. SUDA, T., F. TOZAWA, T. USHIYAMA, N. TOMORI, T. SUMITOMO, Y. NAKAGAMI, M. YAMADA, H. DEMUA, AND K. SHIZUME. Effects of protein kinase-C-related adrenocorticotropin secretagogues and interleukin-1 on proopiomelanocortin gene expression in rat anterior pituitary cells. Endocrinology 124: 1444– 1449, 1989. 826. SUGIMOTO, Y., R. SHIGEMOTO, T. NAMBA, M. NEGISHI, N. MIZUNO, S. NARUMIYA, AND A. ICHIKAWA. Distribution of the messenger RNA for the prostaglandin E receptor subtype EP3 in the mouse central nervous system. Neuroscience 62: 919–928, 1994. 827. SUNDAR, S. K., M. A. CIERPIAL, L. S. KAMARAJU, S. LONG, S. HSIEH, C. LORENZ, M. AARON, J. C. RITCHIE, AND J. M. WEISS. Human immunodeficiency virus glycoprotein (gp120) infused into rat brain induces interleukin-1 to elevate pituitary-adrenal activity and decrease peripheral cellular immune responses. Proc. Natl. Acad. Sci. USA 88: 11246–11250, 1991. Volume 79 January 1999 REGULATION OF HPA AXIS BY CYTOKINES / 9j0c$$oc11 P13-8 865. 866. 867. 868. 869. 870. 871. 872. 873. 874. 875. 876. 877. 878. 879. 880. 881. 882. 11-25-98 11:16:36 typic plasticity of CRF neurons during stress. Ann. NY Acad. Sci. 697: 39–52, 1993. TINGSBORG, S., M. ZETTERSTROM, K. ALHEIM, H. HASANVAN, M. SCHULTZBERG, AND T. BARTFAI. Regionally specific induction of ICE mRNA and enzyme activity in the rat brain and adrenal gland by LPS. Brain Res. 712: 153–158, 1996. TINGSBORG, S., M. ZIOLKOWSKA, M. ZETTERSTROM, H. HASANVAN, AND T. BARTFAI. Regulation of ICE activity and ICE isoforms by LPS. Mol. Psychiatry 2: 122–124, 1997. TOMINAGA, T., J. FUKATA, Y. NAITO, T. USUI, N. MURAKAMI, M. FUKUSHIMA, Y. NAKAI, Y. HIRAI, AND H. IMURA. Prostaglandin-dependent in vitro stimulation of adrenocortical steroidogenesis by interleukins. Endocrinology 128: 526–531, 1991. TOMOZAWA, Y., T. INOUE, AND M. SATOH. Expression of type I interleukin-1 receptor mRNA and its regulation in cultured astrocytes. Neurosci. Lett. 195: 57–60, 1995. TORIGUE, K., S. USHIO, T. OKURA, S. S. KOBAYASHI, M. TANIAI, T. KUNIKATA, T. MURAKAMI, O. SANOU, H. KOJIMA, M. FUJII, T. OHTA, M. IKEDA, H. IKEGAMI, AND M. KURIMOTO. Purification and characterization of the human interleukin-18 receptor. J. Biol. Chem. 272: 25737–25742, 1997. TORRES, G., S. LEE, AND C. RIVIER. Ontogeny of the rat hypothalamic nitric oxide synthase and colocalization with neuropeptides. Mol. Cell. Neurosci. 4: 155–163, 1993. TOSATO, G., AND K. D. JONES. Interleukin-1 induces interleukin6 production in peripheral blood monocytes. Blood 75: 1305–1310, 1990. TRACEY, D. E., AND E. B. DE SOUZA. Identification of interleukin1 receptors in mouse pituitary cell membranes and AtT-20 pituitary tumor cells. Soc. Neurosci. Abstr. 14: 1052, 1988. TSAGARAKIS, S., G. GILLIES, L. H. REES, M. BESSER, AND A. GROSSMAN. Interleukin-1 directly stimulates the release of corticotrophin releasing factor from rat hypothalamus. Neuroendocrinology 49: 98–101, 1989. TSAGARAKIS, S., G. KONTOGEORGOS, P. GIANNOU, N. THALASSINOS, J. WOOLLEY, G. M. BESSER, AND A. GROSSMAN. Interleukin-6, a growth promoting cytokine, is present in human adenomas: an immunocytochemical study. Clin. Endocrinol. 37: 163–167, 1992. TSIEN, J. Z., D. F. CHEN, D. GERBER, C. TOM, E. H. MERCER, D. J. ANDERSON, M. MAYFORD, E. R. KANDEL, AND S. TONEGAWA. Subregion- and cell type-restricted gene knockout in mouse brain. Cell 87: 1317–1326, 1996. TSIGOS, C., D. A. PAPANICOLAOU, R. DEFENSOR, C. S. MITSIADIS, I. KYROU, AND G. P. CHROUSOS. Dose effects of recombinant interleukin-6 on pituitary hormone secretion and energy expenditure. Neuroendocrinology 66: 54–62, 1997. TSUBOKURA, S., Y. WATANABE, H. EHARA, K. IMAMURA, O. SUGIMOTO, H. KAGAMIYAMA, S. YAMAMOTO, AND O. HAYAISHI. Localization of prostaglandin endoperoxide synthase in neurons and glia in monkey brain. Brain Res. 543: 15–24, 1991. TUNKEL, A. R., S. W. ROSSER, E. J. HANSEN, AND W. M. SCHELD. Blood-brain barrier alterations in bacterial meningitis: development of an in vitro model and observations on the effects of lipopolysaccharide. In Vitro Cell. Dev. Biol. 27: 113–120, 1991. TURNBULL, A. V., R. C. DOW, S. J. HOPKINS, A. WHITE, G. FINK, AND N. J. ROTHWELL. Mechanism of the activation of the pituitary-adrenal axis by tissue injury in the rat. Psychoneuroendocrinology 19: 165–178, 1994. TURNBULL, A. V., S. LEE, AND C. RIVIER. Mechanisms of hypothalamic pituitary-adrenal axis stimulation by immune signals in the adult rat. Ann. NY Acad. Sci. 840: 434–443, 1998. TURNBULL, A. V., F. J. PITOSSI, J.-J. LEBRUN, S. LEE, J. C. MELTZER, D. M. NANCE, A. DEL REY, H. O. BESEDOVSKY, AND C. RIVIER. Inhibition of tumor necrosis factor-a (TNF-a) action within the central nervous system markedly reduces the plasma adrenocorticotropin response to peripheral local inflammation in rats. J. Neurosci. 17: 3262–3273, 1997. TURNBULL, A. V., AND C. RIVIER. Brain-periphery connections: do they play a role in mediating the effect of centrally injected interleukin-1b on gonadal function? Neuroimmunomodulation 2: 224–235, 1995. pra APS-Phys Rev Downloaded from on April 23, 2014 846. TAKAO, T., C. TOJO, T. NISHIOKA, H. KUROKAWA, T. TAKEMURA, K. HASHIMOTO, AND E. B. DE SOUZA. Reciprocal modulation of corticotropin-releasing factor and interleukin-1 receptors following ether-laparotomy stress in the mouse. Brain Res. 660: 170–174, 1994. 847. TAKAO, T., C. TOJO, T. NISHIOKA, S. MAKINO, K. HASHIMOTO, AND E. B. DE SOUZA. Stress-induced upregulation of pituitary interleukin-1 receptors is mediated by corticotropin-releasing factor. Life Sci. 59: 165–168, 1996. 848. TAKAO, T., D. E. TRACEY, W. M. MITCHELL, AND E. B. DE SOUZA. Interleukin-1 receptors in mouse brain: characterization and neuronal localization. Endocrinology 127: 3070–3078, 1990. 849. TAKE, S., Y. KANEMITSU, T. YASAKA, T. KATAFUCHI, T. HORI, AND F. ECKENSTEIN. Immobilization stress modulates the expression of interferon-g mRNA in the mouse (Abstract). Proc. Annu. Meet. Soc. Neurosci. 26th Washington DC 1996, p. 336.18. 850. TAKEDA, K., H. TSUTSUI, T. YOSHIMOTO, O. ADACHI, N. YOSHIDA, T. KISHIMOTO, H. OKAMURA, K. NAKANISHI, AND S. AKIRA. Defective NK cell activity and Th1 response in IL-18-deficient mice. Immunity 8: 383–390, 1998. 851. TARTAGLIA, L. A., R. F. WEBER, I. S. FIGARI, C. REYNOLDS, M. A. PALLADINO, AND D. V. GOEDDEL. The two different receptors for tumor necrosis factor mediate distinct cellular responses. Proc. Natl. Acad. Sci. USA 88: 9292–9296, 1991. 852. TATAKI, A., Q. H. HUANG, A. SOMOGYVARI-VIGH, AND A. ARIMURA. Immobilization stress may increase plasma interleukin-6 via central and peripheral catecholamines. Neuroimmunomodulation 1: 335–342, 1994. 853. TATSUNO, I., A. SOMOGYVARI-VIGH, K. MIZUNO, P. E. GOTTSCHALL, H. HIDAKA, AND A. ARIMURA. Neuropeptide regulation of interleukin-6 production from the pituitary: stimulation by adenylate cyclase activating polypeptide and calcitonin generelated peptide. Endocrinology 129: 1797–1804, 1991. 854. TAYLOR, A. D., H. D. LOXLEY, R. J. FLOWER, AND J. C. BUCKINGHAM. Immunoneutralization of lipocortin 1 reverses the acute inhibitory effects of dexamethasone on the hypothalamo-pituitaryadrenocortical responses to cytokines in the rat in vitro and in vivo. Neuroendocrinology 62: 19–31, 1995. 855. TCHELINGERIAN, J.-L., M. MONGUE, F. LE SAUX, B. ZALC, AND C. JACQUE. Differential oligodendrocyte expression of the tumor necrosis factor receptors in vivo and in vitro. J. Neurochem. 65: 2377–2380, 1995. 856. TERADA, Y., H. SINOMIYA, AND M. NAKANO. Defect of calmodulin-binding protein expression of interleukin-1 gene by LPS-nonresponder C3H/HeJ mouse macrophages. Biochem. Biophys. Res. Commun. 158: 723–729, 1989. 857. TERAO, A., H. KITAMURA, A. ASANO, M. KOBAYASHI, AND M. SAITO. Roles of prostaglandins D2 and E2 in interleukin-1-induced activation of norepinephrine turnover in the brain and peripheral organs of rats. J. Neurochem. 65: 2742–2747, 1995. 858. TERAO, A., M. OIKAWA, AND M. SAITO. Cytokine-induced change in hypothalamic norepinephrine turnover: involvement of corticotropin-releasing hormone and prostaglandins. Brain Res. 622: 257–261, 1993. 859. TERAO, A., M. OIKAWA, AND M. SAITO. Tissue-specific increase in norepinephrine turnover by central interleukin-1, but not by interleukin-6, in rats. Am. J. Physiol. 266 (Regulatory Integrative Comp. Physiol. 35): R400–R404, 1994. 860. TERRAZZINO, S., C. PEREGO, AND M. G. DE SIMONI. Noradrenaline release in hypothalamus and ACTH secretion induced by central interleukin-1b. Neuroreport 6: 2465–2468, 1995. 861. THOMPSON, N. L., K. C. FLANDERS, J. M. SMITH, L. R. ELLINGSWORTH, A. B. ROBERTS, AND M. B. SPORN. Expression of transforming growth factor beta 1 in specific cells and tissues of adult and neonatal mice. J. Cell Biol. 108: 661–669, 1989. 862. THOMSON, A. The Cytokine Handbook. London: Academic, 1991. 863. TILDERS, F. J. H., R. H. DE RIJK, A.-M. VAN DAM, V. A. VINCENT, K. SCHOTANUS, AND J. H. A. PERSOONS. Activation of the hypothalamus-pituitary-adrenal axis by bacterial endotoxins: routes and intermediate signals. Psychoneuroendocrinology 19: 209–232, 1994. 864. TILDERS, F. J. H., E. D. SCHMIDT, AND D. C. E. DE GOEIJ. Pheno- 67 68 ANDREW V. TURNBULL AND CATHERINE L. RIVIER / 9j0c$$oc11 P13-8 902. 903. 904. 905. 906. 907. 908. 909. 910. 911. 912. 913. 914. 915. 916. 917. 11-25-98 11:16:36 terleukin-1b in ramified microglia in rat brain: a light and electron microscopic study. Neuroscience 65: 815–826, 1995. VAN DAM, A.-M., M. BROUNS, S. LOUISSE, AND F. BERKENBOSCH. Appearance of interleukin-1 in macrophages and in ramified microglia in the brain of endotoxin-treated rats: a pathway for the induction of non-specific symptoms of sickness? Brain Res. 588: 291–296, 1992. VAN DAM, A. M., M. BROUNS, W. MAN-A-HING, AND F. BERKENBOSCH. Immunocytochemical detection of prostaglandin E2 in microvasculature and in neurons of rat brain after administration of bacterial endotoxin. Brain Res. 613: 331–336, 1993. VAN DAM, A.-M., H. E. DE VRIES, J. KUIPER, F. J. ZIJLSTRA, E. G. DE BOER, F. J. TILDERS, AND F. BERKENBOSCH. Interleukin-1 receptors on rat brain endothelial cells: a role in neuroimmune interaction? FASEB J. 10: 351–356, 1996. VAN DAM, M., J. MULLBERG, H. SCHOOLTINK, T. STOYAN, J. P. J. BRAKENHOFF, L. GRAEVE, P. C. HEINRICH, AND S. ROSE-JOHN. Structure-function analysis of interleukin-6 utilizing human/murine chimeric molecules. J. Biol. Chem. 268: 15285– 15290, 1993. VAN DER MEER, M. J. M., A. R. M. N. HERMUS, G. J. PESMAN, AND C. G. J. SWEEP. Effects of cytokines on pituitary b-endorphin and adrenal corticosterone release in vitro. Cytokine 8: 238–247, 1996. VAN DER MEER, M. J. M., C. G. J. F. SWEEP, G. J. PESMAN, G. F. BORM, AND A. R. M. N. HERMUS. Synergism between IL-1b and TNF-a on the activity of the pituitary-adrenal axis and on food intake of rats. Am. J. Physiol. 268 (Endocrinol. Metab. 31): E551– E557, 1995. VAN DER MEER, M. J. M., C. G. J. F. SWEEP, G. J. PESMAN, F. J. H. TILDERS, AND A. R. M. M. HERMUS. Chronic stimulation of the hypothalamus-pituitary-adrenal axis in rats by interleukin 1b: central and peripheral mechanisms. Cytokine 8: 910–919, 1996. VAN DER MEER, M. J. M., C. G. J. SWEEP, C. E. M. RIJNKELS, G. J. PESMAN, F. J. H. TILDERS, P. W. C. KLOPPENBORG, AND A. R. M. M. HERMUS. Acute stimulation of the hypothalamic-pituitary-adrenal axis by IL-1b, TNFa and IL-6: a dose response study. J. Endocrinol. Invest. 19: 175–182, 1996. VAN GOOL, J., H. VAN VUGT, M. HELLE, AND L. A. AARDEN. The relation among stress, adrenalin, interleukin-6 and acute phase proteins in the rat. Clin. Immunol. Immunopathol. 57: 200–210, 1990. VANKELOM, H., P. CARMELIAT, H. HEREMANS, J. VAN DAMME, R. DIJKMANS, A. BILLIAU, AND C. DENEF. Interferon gamma inhibits stimulated adrenocorticotropin, prolactin, and growth hormone secretion in normal rat anterior pituitary cell cultures. Endocrinology 126: 2919–2926, 1990. VANKELECOM, H., P. CARMELIET, J. VAN DAMME, A. BILLIAU, AND C. DENEF. Production of interleukin-6 by folliculo-stellate cells of the anterior pituitary gland in a histiotypic cell aggregate culture system. Neuroendocrinology 49: 102–106, 1989. VANKELECOM, H., P. MATTHYS, J. VAN DAMME, H. HEREMANS, A. BILLIAU, AND C. DENEF. Immunocytochemical evidence that S-100-positive cells of the mouse anterior pituitary contain interleukin-6 immunoreactivity. J. Histochem. Cytochem. 41: 151–156, 1993. VEENING, J. G., M. J. M. VAN DER MEER, H. JOOSTEN, A. R. M. N. HERMUS, C. E. M. RIJNNKELS, L. M. GEERAEDTS, AND C. G. J. SWEEP. Intravenous administration of interleukin-1 beta induces Fos-like immunoreactivity in corticotropin-releasing hormone neurones in the paraventricular hypothalamic nucleus of the rat. J. Chem. Neuroanat. 6: 391–397, 1993. VELKENIERS, B., P. VERGANI, J. TROUILLAS, J. D’HAENS, R. J. HOOGHE, AND E. L. HOOGHE-PETERS. Expression of IL-6 mRNA in normal rat and human pituitaries and in human pituitary adenomas. J. Histochem. Cytochem. 42: 67–76, 1994. VELLUCCI, S. V., R. F. PARROT, R. F. DA COSTA, S. OHKURA, AND K. M. KENDRICK. Increased body temperature, cortisol secretion, and hypothalamic expression of c-fos, corticotropin releasing hormone and interleukin-1b, following central administration of interleukin-1b in the sheep. Brain Res. 29: 64–70, 1995. VILLAR, M. J., S. CECCATELLI, K. BEDECS, T. BARTFAI, D. pra APS-Phys Rev Downloaded from on April 23, 2014 883. TURNBULL, A. V., AND C. RIVIER. Regulation of the HPA axis by cytokines. Brain Behav. Immun. 9: 253–275, 1995. 884. TURNBULL, A. V., AND C. RIVIER. Corticotropin-releasing factor, vasopressin and prostaglandins mediate, and nitric oxide restrains, the HPA axis response to acute local inflammation in the rat. Endocrinology 137: 455–463, 1996. 885. TURNBULL, A. V., AND C. RIVIER. Cytokine effects on neuroendocrine axes: influence of nitric oxide and carbon monoxide. In: Cytokines in the Nervous System (Neuroscience Intelligence Unit), edited by N. J. Rothwell. Heidelberg, Germany: SpringerVerlag, 1996, p. 93–116. 886. TURNBULL, A. V., AND C. RIVIER. Cytokines within the neuroendocrine system. Curr. Opin. Endocrinol. Diabetes 3: 149–156, 1996. 887. TURNBULL, A. V., AND C. RIVIER. Selective inhibitors of nitric oxide synthase (NOS) implicate a constitutive isoform of NOS in the regulation of interleukin-1-induced ACTH secretion in rats. Endocrine 5: 135–145, 1996. 888. TURNBULL, A. V., AND C. RIVIER. Corticotropin-releasing factor (CRF) and endocrine responses to stress: CRF receptors, binding protein and related peptides. Proc. Soc. Exp. Biol. Med. 215: 1– 10, 1997. 889. TURNBULL, A. V., AND C. RIVIER. Intracereboventricular (icv) passive immunization I: the effect of icv administration of an antisera to tumor necrosis factor-a on the plasma ACTH response to lipopolysaccharide in rats. Endocrinology 139: 119–127, 1998. 890. TURNBULL, A. V., AND C. RIVIER. Intracereboventricular passive immunization. II. Intracerebroventricular infusion of neuropeptide antisera can inhibit neuropeptide signaling in peripheral tissues. Endocrinology 139: 128–136, 1998. 891. TURNBULL, A. V., W. VALE, AND C. RIVIER. Urocortin, a corticotropin-releasing factor-related mammalian peptide, inhibits edema due to thermal injury in rats. Eur. J. Pharmacol. 303: 213–216, 1996. 892. TURNBULL, A. V., J. VAUGHAN, J. RIVIER, W. VALE, AND C. RIVIER. Regulation of adrenocorticotropin secretion in the rat by the novel mammalian neuropeptide, urocortin. Proc. Int. Congr. Endocrinol. 10th San Francisco CA 1996, P. 3–534. 893. UEHARA, A., S. GILLIS, AND A. ARIMURA. Effects of interleukin1 on hormone release from rat pituitary cells in primary culture. Neuroendocrinology 45: 343–347, 1987. 894. UEHARA, A., P. E. GOTTSCHALL, R. R. DAHL, AND A. ARIMURA. Interleukin-1 stimulates ACTH release by an indirect action which requires endogenous corticotropin-releasing factor. Endocrinology 121: 1580–1582, 1987. 895. UETA, Y., A. LEVY, H. S. CHOWDREY, AND S. L. LIGHTMAN. S100 antigen positive folliculostellate cells are not the major source of IL-6 gene expression in human pituitary adenomas. J. Neuroendocrinol. 7: 467–474, 1995. 896. UR, E., P. D. WHITE, AND A. GROSSMAN. Hypothesis: cytokines may be activated to cause depressive illness and chronic fatigue syndrome. Eur. Arch. Psychiatry Clin. Neurosci. 241: 317–322, 1992. 897. VALE, W., J. RIVIER, J. VAUGHAN, R. MCCLINTOCK, A. CORRIGAN, W. WOO, D. KARR, AND J. SPIESS. Purification and characterization of an FSH releasing protein from porcine ovarian follicular fluid. Nature 321: 776–779, 1986. 898. VALE, W., J. SPEISS, C. RIVIER, AND J. RIVIER. Characterization of a 41-amino acid residue ovine hypothalamic peptide that stimulates the secretion of corticotropin and b-endorphin. Science 213: 1394–1397, 1981. 899. VALLIERES, L., S. LACROIX, AND S. RIVEST. Influence of interleukin-6 on neural activity and transcription of the gene encoding corticotropin-releasing factor in the rat brain: an effect depending upon the route of administration. Eur. J. Neurosci. 9: 1461–1472, 1997. 900. VALLIERES, L., AND L. RIVEST. Regulation of the genes encoding interleukin-6, its receptor, and gp130 in the rat brain in response to the immune activator lipopolysaccharide and the proinflammatory cytokine interleukin-1b. J. Neurochem. 69: 1668–1683, 1997. 901. VAN DAM, A.-M., J. BAUER, F. J. H. TILDERS, AND F. BERKENBOSCH. Endotoxin-induced appearance of immunoreactive in- Volume 79 January 1999 918. 919. 920. 921. 922. 923. 924. 926. 927. 928. 929. 930. 931. 932. 933. 934. 935. BREDT, S. H. SNYDER, AND T. HOKFELT. Upregulation of nitric oxide synthase and galanin message-associated peptide in hypothalamic magnocellular neurons after hypophysectomy. Immunohistochemical and in situ hybridization studies. Brain Res. 650: 219–228, 1994. VILLAR, M. J., S. CECCATELLI, M. RONNQVIST, AND T. HOKFELT. Nitric oxide synthase increases in hypothalamic magnocellular neurones after salt loading in the rat. An immunohistochemical and in situ hybridization study. Brain Res. 644: 273–281, 1994. VINCENT, S. R., AND H. KIMURA. Histochemical mapping of the nitric oxide synthase in the rat brain. Neuroscience 46: 755–784, 1992. VITI, A., M. MUSCETLOLA, L. PAULESU, V. BOCCI, AND A. ALMI. Effect of exercise on plasma interferon levels. J. Appl. Physiol. 59: 426–428, 1985. VLASKOVSKA, M., G. HERRTING, AND W. KNEPEL. Adrenocorticotropin and b-endorphin release from rat adenohypophysis in vitro: inhibition by prostaglandin E2 formed locally in response to vasopressin and corticotropin releasing factor. Endocrinology 115: 895–903, 1984. WADA, Y., M. SATO, M. NIIMI, M. TAMAKI, T. ISHIDA, AND J. TAKAHARA. Inhibitory effect of interleukin-1 on growth hormone secretion in conscious male rats. Endocrinology 136: 3936–3941, 1995. WAGUESPACK, P. J., W. A. BANKS, AND A. J. KASTIN. Interleukin-2 does not cross the blood-brain barrier by a saturable transport system. Brain Res. Bull. 34: 103–109, 1994. WAN, W., L. JANZ, C. Y. VRIEND, C. M. SORENSON, A. H. GREENBERG, AND D. M. NANCE. Differential induction of c-fos immunoreactivity in hypothalamus and brain stem nuclei following central and peripheral administration of endotoxin. Brain Res. Bull. 32: 581–587, 1993. WAN, W., L. WETMORE, C. M. SORENSON, A. H. GREENBERG, AND D. M. NANCE. Neural and biochemical mediators of endotoxin and stress-induced c-fos expression in the rat brain. Brain Res. Bull. 34: 7–14, 1994. WANG, Z., S. G. REN, AND S. MELMED. Hypothalamic and pituitary leukemia inhibitory factor gene expression in vivo: a novel endotoxin-inducible neuro-endocrine interface. Endocrinology 137: 2947–2953, 1996. WATANABE, D., R. YOSHIMURA, M. KHALIL, K. YOSHIDA, T. KISHIMOTO, T. TAGA, AND H. KIYAMA. Characteristic localization of gp130 (the signal transducing receptor component used in common for IL-6/IL-11/CNTF/OSM) in the rat brain. Eur. J. Neurosci. 8: 1630–1640, 1996. WATANABE, T., A. MORIMOTO, K. MORIMOTO, T. NAKAMORI, AND N. MURAKAMI. ACTH release induced in rats by noradrenaline is mediated by prostaglandin E2. J. Physiol. (Lond.) 443: 431– 439, 1991. WATANABE, T., A. MORIMOTO, AND N. MURAKAMI. Threshold dose of interleukin-1b for induction of an ACTH response is higher than a febrile response. Pflu¨gers Arch. 419: 629–631, 1990. WATANABE, T., A. MORIMOTO, AND N. MURAKAMI. ACTH response in rats during biphasic fever induced by interleukin-1. Am. J. Physiol. 261 (Regulatory Integrative Comp. Physiol. 30): R1104–R1108, 1991. WATANABE, T., A. MORIMOTO, Y. SAKATA, AND N. MURAKAMI. ACTH response induced by interleukin-1 is mediated by CRF secretion stimulated by hypothalamic PGE. Experientia 46: 481– 484, 1990. WATANABE, T., A. MORIMOTO, N. TAN, T. MAKISUMI, S. SHIMADA, T. NAKAMORI, AND N. MURAKMI. ACTH response induced in capsaicin-desensitized rats by intravenous injection of interleukin-1 or prostaglandin E. J. Physiol. (Lond.) 475: 139– 145, 1994. WATANABE, Y., Y. WATANABE, K. HAMADA, M.-C. BOMMELARBAYT, F. DRAY, T. KANEKO, N. YUMOTO, AND O. HAYAISHI. Distinct localization of prostaglandin D2, E2 and F2a binding sites in the monkey brain. Brain Res. 478: 143–148, 1989. WATANABE, Y., Y. WATANABE, AND O. HAYAISHI. Quantitative autoradiographic localization of prostaglandin E2 binding sites in monkey diencephalon. J. Neurosci. 8: 2003–2010, 1988. WATANOBE, H., R. NASUSHITA, AND K. TAKEBE. A study of the / 9j0c$$oc11 P13-8 936. 937. 938. 939. 940. 941. 942. 943. 944. 945. 946. 947. 948. 949. 950. 951. 952. 11-25-98 11:16:36 69 role of circulating prostaglandin E2 in the adrenocorticotropin response to intravenous administration of interleukin-1b in the rat. Neuroendocrinology 62: 596–600, 1995. WATANOBE, H., S. SASAKI, AND K. TAKEBE. Evidence that intravenous administration of interleukin-1 stimulates corticotropin releasing hormone secretion in the median eminence of freely moving rats: estimation by push pull perfusion. Neurosci. Lett. 133: 7–10, 1991. WATANOBE, H., S. SASAKI, AND K. TAKEBE. Role of prostaglandins E1, E2 and F2 alpha in the brain in interleukin-1 beta-induced adrenocorticotropin secretion in the rat. Cytokine 7: 710–712, 1995. WATANOBE, H., AND K. TAKEBE. Intravenous administration of tumor necrosis factor-a stimulates corticotropin-releasing hormone secretion in the push-pull cannulated median eminence of freely moving rats. Neuropeptides 22: 81–84, 1992. WATANOBE, H., AND K. TAKEBE. Intrahypothalamic perfusion with interleukin-1-beta stimulates the local release of corticotropin-releasing hormone and arginine vasopressin and plasma adrenocorticotropin in freely moving rats: a comparative perfusion of the paraventricular nucleus and the median eminence. Neuroendocrinology 57: 593–599, 1993. WATANOBE, H., AND K. TAKEBE. Effects of intravenous administration of interleukin-1 beta on the release of prostaglandin E2, corticotropin-releasing factor, and arginine vasopressin in several hypothalamic areas of freely moving rats: estimation by push-pull perfusion. Neuroendocrinology 60: 8–15, 1994. WATKINS, L. R., L. E. GOEHLER, J. RELTON, M. T. BREWER, AND S. F. MAIER. Mechanisms of tumor necrosis factor-a (TNFa) hyperalgesia. Brain Res. 692: 244–250, 1995. WATKINS, L. R., L. E. GOEHLER, J. K. RELTON, N. TARTAGLIA, L. SILBERT, D. MARTIN, AND S. F. MAIER. Blockade of interleukin-1 induced hyperthermia by subdiaphragmatic vagotomy: evidence for vagal mediation of immune brain communication. Neurosci. Lett. 183: 27–31, 1995. WATKINS, L. R., S. F. MAIER, AND L. E. GOEHLER. Cytokine-tobrain communication: a review and analysis of alternative mechanisms. Life Sci. 57: 1011–1026, 1995. WATKINS, L. R., E. P. WIERTELAK, L. E. GOEHELER, K. MOONEY-HEIBERGER, J. MARTINEZ, L. FURNESS, K. P. SMITH, AND S. F. MAIER. Neurocircuitry of illness-induced hyperalgesia. Brain Res. 639: 283–299, 1994. WATKINS, L. R., E. P. WIERTELAK, L. E. GOEHLER, K. P. SMITH, D. MARTIN, AND S. F. MAIER. Characterization of cytokine-induced hyperalgesia. Brain Res. 654: 15–26, 1994. WEBER, M. M., P. MICHL, C. J. AUERNHAMMER, AND D. ENGELHARDT. Interleukin-3 and interleukin-6 stimulate cortisol secretion from adult human adrenocortical cells. Endocrinology 138: 2207–2210, 1997. WEBSTER, E. L., D. E. TRACEY, AND E. B. DE SOUZA. Upregulation of interleukin-1 receptors in mouse AtT-20 pituitary cells following treatment with corticotropin-releasing factor. Endocrinology 129: 2796–2798, 1991. WEI, X.-Q., I. G. CHARLES, A. SMITH, J. URE, G. J. FENG, F. P. HUANG, D. XU, W. MULLER, S. MONCADA, AND F. Y. LIEW. Altered immune responses in mice lacking inducible nitric oxide synthase. Nature 375: 408–411, 1995. WEIDENFELD, J., O. ABRAMSKY, AND H. OVADIA. Evidence for the involvement of the central nervous adrenergic system in interleukin 1-induced adrenocortical response. Neuropharmacology 28: 1411–1414, 1989. WEIDENFELD, J., M. CRUMEYROLLE-ARIAS, AND F. HAOUR. Effect of bacterial endotoxin and interleukin-1 on prostaglandin biosynthesis by the hippocampus of mouse brain: role of interleukin-1 receptors and glucocorticoids. Neuroendocrinology 62: 39– 46, 1995. WEIGENT, D. A., J. B. BAXTER, W. E. WEAR, L. R. SMITH, K. L. BOST, AND J. E. BLALOCK. Production of immunoreactive growth hormone by mononuclear leukocytes. FASEB J. 2: 2812–2818, 1988. WEIGENT, D. A., AND J. E. BLALOCK. Interaction beteen neuroendocrine and immune systems: common hormones and receptors. Immunol. Rev. 100: 79–108, 1987. pra APS-Phys Rev Downloaded from on April 23, 2014 925. REGULATION OF HPA AXIS BY CYTOKINES 70 ANDREW V. TURNBULL AND CATHERINE L. RIVIER / 9j0c$$oc11 P13-8 973. 974. 975. 976. 977. 978. 979. 980. 981. 982. 983. 984. 985. 986. 987. 988. 989. 990. 991. 992. 11-25-98 11:16:36 I receptor mRNA in rat brain. Neuroimmunomodulation 1: 110– 115, 1994. WONG, M. L., AND J. LICINO. Localization of stem cell factor mRNA in adult rat hippocampus. Neuroimmunomodulation 1: 181–187, 1994. WONG, M. L., V. RETTORI, A. AL-SHEKHLEE, P. B. BONGIORNO, G. CANTEROS, S. M. MCCANN, P. W. GOLD, AND J. LICINIO. Inducible nitric oxide synthase gene expression in the brain during systemic inflammation. Nature Med. 2: 581–584, 1996. WOOD, C. E., J. SHINSAKO, AND M. F. DALLMAN. Comparison of canine corticosteroid responses to mean and phasic increases in ACTH. Am. J. Physiol. 242 (Endocrinol. Metab. 5): E102–E108, 1982. WOOLF, P. D., C. COX, M. KELLY, D. NICHOLS, J. V. MCDONALD, AND R. W. HAMILL. The adrenocortical response to brain injury: correlation with the severity of neurological dysfunction, effects of intoxication, and patient outcome. Alcohol. Clin. Exp. Res. 14: 917–921, 1990. WUCHERPFENNIG, K. W., J. NEWCOMBE, H. LI, C. KEDDY, M. L. CUZNER, AND D. A. HAFLER. T cell receptor Valpha-Vbeta repertoire and cytokine gene expression in active multiple sclerosis lesions. J. Exp. Med. 175: 993–1002, 1992. WUSTEMAN, M., D. G. D. WIGHT, AND M. ELIA. Protein metabolism after injury with turpentine: a rat model for clinical trauma. Am. J. Physiol. 259 (Endocrinol. Metab. 22): E763–E769, 1990. XIA, M., S. QIN, M. MCNAMARA, C. MACKAY, AND B. T. HYMAN. Interleukin-8 receptor B immunoreactivity in brain and neuritic placques of Alzheimer’s disease. Am. J. Pathol. 150: 1267–1274, 1997. XIE, W., J. G. CHIPMAN, D. L. ROBERTSON, R. L. ERIKSON, AND D. L. SIMMONS. Expression of a mitogen-responsive gene encoding prostaglandin synthase is regulated by mRNA splicing. Proc. Natl. Acad. Sci. USA 88: 2692–2696, 1991. YABUUCHI, K., E. MARUTA, M. MINAMI, AND M. SATOH. Induction of interleukin-1b mRNA in the hypothalamus following subcutaneous injections of Formalin into the rat hind paws. Neurosci. Lett. 207: 109–112, 1996. YABUUCHI, K., M. MINAMI, S. KATSUMATA, AND M. SATOH. Localization of type I interleukin-1 receptor mRNA in the rat brain. Brain Res. 27: 27–36, 1994. YAMADA, T., M. A. HORISBERGER, N. KAWAGUCHI, I. MOROO, AND T. TOYODA. Immunohistochemistry using antibodies to alpha-interferon and its induced protein, MxA, in Alzheimer’s and Parkinson’s disease brain tissue. Neurosci. Lett. 181: 61–64, 1994. YAMADA, T., AND I. YAMANAKA. Microglial localization of alphainterferon receptor in human brain tissues. Neurosci. Lett. 189: 73–76, 1995. YAMAGATA, K., K. I. ANDREASSON, W. E. KAUFMANN, C. A. BARNES, AND P. F. WORLEY. Expression of a mitogen-inducible cyclooxygenase in brain neurons: regulation by synaptic activity and glucocorticoids. Neuron 11: 371–386, 1993. YAMAGUCHI, M., K. KOIKE, N. MATSUZAKI, Y. YOSHIMOTO, T. TAMIGUSHI, A. MIYAKE, AND O. TANIZAWA. The interferon family stimulates the secretion of prolactin and interleukin-6 by the pituitary gland in vitro. J. Endocrinol. Invest. 14: 457–461, 1991. YAMAMORI, T. Localization of cholinergic differentiation factor/ leukemia inhibitory factor mRNA in the rat brain and peripheral tissues. Proc. Natl. Acad. Sci. USA 88: 7298–7302, 1991. YAN, H. Q., M. A. BANOS, P. HERREGODTS, R. HOOGHE, AND E. L. HOOGHE-PETERS. Expression of interleukin (IL)-1b, IL-6 and their respective receptors in the normal rat brain and after injury. Eur. J. Immunol. 22: 2963–2971, 1992. YANAGISAWA, K., T. TAKAGI, T. TSUKAMOTO, T. TETSUKA, AND S. TOMINAGA. Presence of a novel primary response gene ST2L, encoding a product highly similar to the interleukin-1 receptor type 1. FEBS Lett. 318: 83–87, 1993. YAO, J., AND R. W. JOHNSON. Induction of interleukin-1 beta converting enzyme (ICE) in murine microglia by lipopolysacchairde. Brain Res. 51: 170–178, 1997. YASIN, S. A., A. COSTA, M. L. FORSLING, AND A. GROSSMAN. Interleukin-1b and interleukin-6 stimulate neurohypophysial hormone release in vitro. J. Neuroendocrinol. 6: 179–184, 1994. YASIN, S. A., A. COSTA, D. HUCKS, M. L. FORSLING, AND A. pra APS-Phys Rev Downloaded from on April 23, 2014 953. WEIGENT, D. A., AND J. E. BLALOCK. Production of peptide hormones and neurotransmitters by the immune system. Chem. Immunol. 69: 1–30, 1997. 954. WEISS, J. M., AND S. K. SUNDAR. Interleukin-1: effects in the central nervous sytem and relevance to AIDS. Clin. Neuropharmacol. 15, Suppl. 1: 661–662, 1992. 955. WESTERMANN, R., M. JOHANNSEN, K. UNSICKER, AND C. GROTHE. Basic fibroblast growth factor (bFGF) immunoreactivity is present in chromaffin cells. J. Neurochem. 55: 285–292, 1990. 956. WETHER, G. A., M. ABATE, A. HOGG, H. CHEESMAN, B. OLDFIELD, D. HARDS, P. HUDSON, B. POWER, K. FREED, AND A. C. HERINGTON. Localization of insulin-like growth factor-I mRNA in rat brain by in situ hybridization: relationship to IGF-I receptors. Mol. Endocrinol. 4: 773–778, 1990. 957. WHITCOMB, R. W., W. M. LINEHAM, L. M. WAHL, AND R. A. KNAZEK. Monocytes stimulate cortisol production by cultured human adrenocortical cells. J. Clin. Endocrinol. Metab. 66: 33–38, 1988. 958. WHITNALL, M. H., R. S. PERLSTEIN, E. H. MOUGEY, AND R. NETA. Effects of interleukin-1 on the stress-responsive and -nonresponsive subtypes of corticotropin-releasing hormone neurosecretory axons. Endocrinology 131: 37–44, 1992. 959. WICK, G. W., Y. HU, S. SCHWARZ, AND G. KROEMER. Immunoendocrine communication via the hypothalamo-pituitary-adrenal axis in autoimmune diseases. Endocr. Rev. 14: 539–563, 1993. 960. WILCOX, J. N., AND R. DERYNCK. Localization of cells synthesizing transforming growth factor-alpha mRNA in the mouse brain. J. Neurosci. 8: 1901–1904, 1988. 961. WILLIAMS, C. A., AND B. L. ALLEN-HOFFMAN. Transforming growth factor-beta 1 stimulates fibronectin production in bovine adrenocortical cells in culture. J. Biol. Chem. 265: 6467–6472, 1990. 962. WILLIAMS, L. M., P. E. BALLMER, L. T. HANNAH, I. GRANT, AND P. J. GARLICK. Changes in regional protein synthesis in rat brain and pituitary after systemic interleukin-1b administration. Am. J. Physiol. 267 (Endocrinol. Metab. 30): E915–E920, 1994. 963. WILT, S., E. MILWARD, J. ZHOU, K. NAGASATO, H. PATTON, R. RUSTEN, D. GRIFFIN, M. O’CONNOR, AND M. DUBOIS-DALCQ. In vitro evidence for a dual role of tumor necrosis factor-a in human immunodeficiency virus type I encephalopathy. Ann. Neurol. 37: 382–394, 1995. 964. WINTER, J. S. D., K. W. GOW, Y. S. PERRY, AND A. H. GREENBERG. A stimulatory effect of interleukin-1 on adrenocortical cortisol secretion mediated by prostaglandins. Endocrinology 127: 1904–1990, 1990. 965. WOLOSKI, B. M. R. N. J., AND J. C. JAMIESON. Rat corticotropin, insulin and thyroid hormone levels during the acute phase response to inflammation. Comp. Biochem. Physiol. 86: 15–19, 1987. 966. WOLOSKI, B. M. R. N. J., E. M. SMITH, W. J. MEYER III, G. M. FULLER, AND J. E. BLALOCK. Corticotropin-releasing activity of monokines. Science 230: 1035–1037, 1985. 967. WOLVERS, D. A., C. MARQUETTE, F. BERKENBOSCH, AND F. HAOUR. Tumor necrosis factor-alpha: specific binding sites in rodent brain and pituitary gland. Eur. Cytokine Netw. 4: 377–381, 1993. 968. WONG, G. H. W., L. A. TARTAGLIA, M. S. LEE, AND D. V. GOEDDEL. Antiviral activity of tumor necrosis is signalled through the 55-kDa type 1 receptor. J. Immunol. 149: 3550–3553, 1992. 969. WONG, M. L., P. B. BONGIORNO, A. AL-SHEKHLEE, A. ESPOSITO, P. KHATRI, AND J. LICINIO. IL-1 beta, IL-1 receptor type I receptor and iNOS gene expression in rat brain vasculature and perivascular areas. Neuroreport 7: 2445–2448, 1996. 970. WONG, M.-L., P. B. BONGIORNO, P. W. GOLD, AND J. LICINIO. Localization of interleukin-1b converting enzyme mRNA in rat brain vasculature: evidence that the genes encoding the interleukin-1 system are constitutively expressed in brain blood vessels. Neuroimmunomodulation 2: 141–148, 1995. 971. WONG, M.-L., P. B. BONGIORNO, V. RETTORI, S. M. MCCANN, AND J. LICINIO. Interleukin- (IL) 1b, IL-1 receptor antagonist, IL10, and IL-13 gene expression in the central nervous system and anterior pituitary during systemic inflammation: pathophysiological implications. Proc. Natl. Acad. Sci. USA 94: 227–232, 1997. 972. WONG, M.-L., AND J. LICINIO. Localization of interleukin 1 type Volume 79 January 1999 993. 994. 995. 996. 997. 998. 999. REGULATION OF HPA AXIS BY CYTOKINES GROSSMAN. Interleukin-induced vasopressin release is inhibited by L-arginine. Ann. NY Acad. Sci. 689: 693–695, 1993. YASIN, S., A. COSTA, P. TRAINER, R. WINDLE, M. L. FORSLING, AND A. GROSSMAN. Nitric oxide modulates the release of vasopressin from rat hypothalamic explants. Endocrinology 133: 1466– 1469, 1993. YOON, D. Y., AND C. A. DINARELLO. Antibodies to domains II and III of the IL-1 receptor accessory protein inhibit IL-1 beta activity but not binding: regulation of IL-1 responses is via type I receptor, not the accessory protein. J. Immunol. 160: 3170–3179, 1998. YOUNG, W. S., III, E. MEZEY, AND R. E. SIEGEL. Quantitative in situ hybridization histochemistry reveals increased levels of corticotropin-releasing factor mRNA after adrenalectomy in rats. Neurosci. Lett. 70: 198–203, 1986. ZALCMAN, S., J. M. GREEN-JOHNSON, L. MURRAY, D. M. NANCE, D. DYCK, H. ANISMAN, AND A. H. GREENBURG. Cytokine-specific central monoamine alterations induced by interleukin-1, -2 and -6. Brain Res. 643: 40–49, 1994. ZALCMAN, S., N. SHANKS, AND H. ANISMAN. Time-dependent variations of central norepinephrine and dopamine following antigen administration. Brain Res. 557: 69–76, 1991. ZANETTI, G., D. HEUMANN, J. GERAIN, J. KOHLER, P. ABBET, C. BARRAS, R. LUCAS, M.-P. GLAUSER, AND J.-D. BAUMGARTNER. Cytokine production after intravenous or peritoneal Gramnegative bacterial challenge in mice. J. Immunol. 148: 1890–1897, 1992. ZELAZOWSKI, P., V. K. PATCHEV, E. B. ZELAZOWSKA, G. P. 1000. 1001. 1002. 1003. 1004. 71 CHROUSOS, P. W. GOLD, AND E. M. STERNBERG. Release of hypothalamic corticotropin-releasing hormone and arginine vasopressin by interleukin-1 beta and alpha MSH: studies in rats with different susceptibility to inflammatory disease. Brain Res. 631: 22–26, 1993. ZHANG, S. C., AND S. FEDEROFF. Cellular localization of stem cell factor and c-kit receptor in the mouse central nervous system. J. Neurosci. Res. 47: 1–15, 1997. ZHENG, H., D. FLETCHER, W. KOZAK, M. JIANG, K. J. HOFMAN, C. A. CONN, D. SOSZYNSKI, C. GRABIEC, M. E. TRUMBAUER, A. SHAW, M. J. KOSTURA, K. STEVENS, H. ROSEN, R. J. NORTH, H. Y. CHEN, M. J. TOCCI, M. J. KLUGER, AND L. H. T. VAN DER PLOEG. Resistance to fever induction and impaired acute-phase response in interleukin-1b-deficient mice. Immunity 3: 9–19, 1995. ZHOU, D., A. W. KUSNECOV, M. R. SHURIN, M. DEPAOLI, AND B. RABIN. Exposure to physical and psychological stressors elevates plasma interleukin-6: relationship to the activation of the hypothalamo-pituitary-adrenal axis. Endocrinology 133: 2523–2530, 1993. ZHOU, D., N. SHANKS, S. E. RIECHMAN, R. LIANG, A. W. KUSNECOV, AND B. S. RABIN. Interleukin-6 modulates interleukin-1and stress-induced activation of the hypothalamic-pituitary-adrenal axis in male rats. Neuroendocrinology 63: 227–236, 1996. ZIELENIEWSKI, W., J. ZIELENIEWSKI, AND H. STEPIEN. Effect of interleukin-1a, IL-1b and IL-1 receptor antibody on the proliferation and steroidogenesis of regenerating rat adrenal cortex. Exp. Clin. Endocrinol. Diabetes 103: 373–377, 1995. Downloaded from on April 23, 2014 / 9j0c$$oc11 P13-8 11-25-98 11:16:36 pra APS-Phys Rev Regulation of the Hypothalamic-Pituitary-Adrenal Axis by Cytokines: Actions and Mechanisms of Action ANDREW V. TURNBULL and CATHERINE L. RIVIER Physiol Rev 79:1-71, 1999. You might find this additional info useful... This article has been cited by 96 other HighWire hosted articles, the first 5 are: Intestinal microbiota and immune function in the pathogenesis of irritable bowel syndrome Yehuda Ringel and Nitsan Maharshak Am J Physiol Gastrointest Liver Physiol, October 15, 2013; 305 (8): G529-G541. 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