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
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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
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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
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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
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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
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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
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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.
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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).
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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
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ANDREW V. TURNBULL AND CATHERINE L. RIVIER
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Interleukin literally means ‘‘between leukocytes.’’
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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-
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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
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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
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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
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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).
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TABLE
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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.
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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
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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
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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-
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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-
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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
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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
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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-
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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
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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
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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
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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
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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
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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
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ANDREW V. TURNBULL AND CATHERINE L. RIVIER
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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.
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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
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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
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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.
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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
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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
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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
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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,
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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
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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.
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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
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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
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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-
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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
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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
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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
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Cytokine
January 1999
REGULATION OF HPA AXIS BY CYTOKINES
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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,
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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
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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
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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
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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
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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-
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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.
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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
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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
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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).
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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
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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,
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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
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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-
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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).
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Activinf
EGF
IFN-a
IFN-g
Anterior Pituitary Cells
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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
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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,
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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
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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-
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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-
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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
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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.
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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).
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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
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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
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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
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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.
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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
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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–
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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
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REGULATION OF HPA AXIS BY CYTOKINES
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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–
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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
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ANDREW V. TURNBULL AND CATHERINE L. RIVIER
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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
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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-
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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
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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
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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
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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
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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
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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.
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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
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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-
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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,
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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-
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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).
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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
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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
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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
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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
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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
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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).
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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.
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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.
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20.
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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.
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