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Neurokinin B: A New Player in Immune/Inflammatory
Stress-Mediated Suppression of Reproduction
Heather J. Billings
Department of Neurobiology and Anatomy, West Virginia University Health Sciences Center,
Morgantown, West Virginia 26506-9128
oth immune/inflammatory and psychosocial stressors
have profound effects on suppressing reproduction.
Suppressing reproduction in times of stress, such as when
fighting infection, or due to other environmental factors
such as overcrowding, is an important shift of survival
functions for a species, especially those with longer gestation periods or parental investment in rearing of offspring (1). Among other effects on reproduction, stress
acts through glucocorticoids to decrease LH pulsatile secretion (2, 3). Immune/inflammatory stress, such as that
induced by lipopolysaccharide (LPS) derived from Gramnegative bacteria, suppresses the GnRH and LH surge during the early preovulatory estradiol rise in sheep (4), and
this suppression is independent of prostaglandins (5). In
contrast, prostaglandins are mediators of LPS-induced
suppression of GnRH and LH pulsatile secretion during
the luteal phase in ewes (6). Cortisol treatment mimics the
suppressive effects of LPS, but blocking cortisol production does not prevent LPS-induced suppression of LH
pulses (7).
Until now, it has not been clear which neural pathways
mediate stress-induced suppression of GnRH and LH.
Neurons in the arcuate nucleus of the hypothalamus coexpress kisspeptin, neurokinin B (NKB), and dynorphin A
(8). Of the peptides produced by the arcuate kisspeptin,
NKB, dynorphin (KNDy) neurons, NKB appears unique
in differentially modulating GnRH and LH secretion
based on the steroid milieu. Both NKB and a selective
neurokinin-3 receptor (NK3R) agonist have differential
effects on GnRH and LH secretion, depending on the gonadal state of the subjects treated (9). For example, in
female gonadal-intact, estradiol-treated rats and sheep,
and pubertal rats, NKB or NK3R agonist treatment in-
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creases GnRH and LH secretion, whereas in ovariectomized rats, these same treatments suppress GnRH or LH
secretion (reviewed in Reference 9). During fasting, another type of stressor, the increase of LH in response to
NK3R agonist treatment is even greater in pubertal rats
compared with ad libitum feeding (10). In contrast, responses to kisspeptin or dynorphin or agonists that bind to
their cognate receptors, G protein-coupled receptor 54
and -opioid receptor (KOR), respectively, are more consistent across the reproductive cycle (8).
In this issue, Grachev et al (11) report the results of a
series of experiments that link the suppression of reproduction by immune/inflammatory stress with the NKB/
NK3R pathway in female rats. They first determined
whether NK3R or KOR, the receptor for which dynorphin
has the greatest affinity, were necessary for the LPS-induced suppression of LH pulses or increases in corticosterone (CORT) concentrations (11). Administration of
the KOR antagonist nor-BNI did not reverse the effects of
LPS on either LH pulsatility or CORT secretion, whereas
the NK3R antagonist (SB222200) did reverse the suppression of LH pulsatility, although CORT remained elevated
(11). This suggests that immune/inflammatory stress acts
upstream of NKB to increase CORT secretion, and the
effects of CORT on LH pulsatility are at least in part mediated through NK3R-containing neurons (11).
Administration of LPS stimulates other factors involved in the immune/inflammatory response, including
prostaglandins and ILs (12). In sheep, blocking prostaglandin synthesis reverses the LPS-induced suppression of
LH in the luteal (6) but not the follicular phase (5). In
women with polycystic ovary syndrome, a disorder including failure to ovulate and development of large cystic
ISSN Print 0013-7227 ISSN Online 1945-7170
Printed in U.S.A.
Copyright © 2014 by the Endocrine Society
Received May 5, 2014. Accepted May 29, 2014.
Abbreviations: CORT, corticosterone; KNDy, kisspeptin/neurokinin B/dynorphin; KOR,
-opioid receptor; LPS, lipopolysaccharide; NKB, neurokinin B; NK3R, neurokinin-3
receptor.
For article see page 2589
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Endocrinology, July 2014, 155(7):2346 –2348
doi: 10.1210/en.2014-1360
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doi: 10.1210/en.2014-1360
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Figure 1. Working model of immune/inflammatory stress effects on
female reproduction at the hypothalamic level. KNDy neurons in the
arcuate nucleus form a local network that can switch between
inhibitory and stimulatory states to synchronize GnRH pulse
generation. Ovarian steroids modulate the balance of peptides
synthesized and released by KNDy neurons for synchronizing GnRH
pulses and may also modulate NKB actions on NK3R-expressing
interneurons between the KNDy and GnRH neurons, accounting for
differential actions of NKB in ovariectomized and ovary-intact females.
During an immune/inflammatory challenge, the hypothalamo-pituitaryadrenal axis is stimulated and CRH afferents to the KNDy neurons also
stimulate NKB release, which leads to positive feedback to CRH
neurons to further stimulate CORT in this pathological state.
E, estrogen; P, progesterone.
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the same arcuate neuron population coexpresses NKB and
dynorphin. A potential role of kisspeptin or its receptor, G
protein-coupled receptor 54, cannot be ruled out.
The present demonstration that CRH neurons are
likely afferent to the NKB/NK3R neurons fits with previous evidence that NKB may be involved in either tonic
GnRH/LH pulsatility (15) or the GnRH/LH surge induction (16) and fits a new piece into the puzzle of how the
immune system interacts with the reproductive system. A
schematic model of how this interaction may occur is illustrated in Figure 1. Whether the NKB/NK3R neurons
involved in this pathway are indeed part of the arcuate
KNDy neuronal population, or another population of
NKB neurons, remains an open question. Likewise, how
NK3R cell populations function in mediating both a rise
in CORT and the CORT-induced suppression of LH pulsatility is an intriguing new question of steroid feedback
regulation. Thus, the current report connects two previously disconnected lines of research on the reproductive
neuroendocrine system, opening exciting new directions
for exploration of this complex system.
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Acknowledgments
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follicles, psychosocial stressors also lead to increased immune system activation as well as an increased cortisol
response compared with normally cycling controls (13).
Taken together, there may be bidirectional interactions of
both the immune system on reproduction and the reproductive system on immune functions. Therefore, it was
necessary to tease apart the effects of other immune/inflammatory mediators from a direct action of CORT on
the reproductive neuroendocrine axis. To determine
whether CORT is a necessary step in the immune/inflammatory suppression of reproductive function, rats were
treated with antagonists to either CRH or arginine vasopressin followed by an NK3R agonist (11). In OVX rats,
the NK3R agonist suppresses LH secretion (14). Neither
the CRH nor arginine vasopressin antagonists attenuated
NK3R agonist-induced suppression of LH (11). Only the
CRH antagonist blocked a CORT rise associated with
NK3R agonist treatment (11). The KOR antagonist in the
study by Grachev et al (11) did not block the NK3R agonist-induced rise in CORT, suggesting at least one pathway for inducing CORT secretion involves NK3R-expressing neurons but not dynorphin or KOR, even though
Address all correspondence and requests for reprints to: Heather
J. Billings, PhD, Department of Neurobiology and Anatomy,
West Virginia University Health Sciences Center, 1 Medical Center Drive, PO Box 9128, Morgantown, WV 26506 –9128. Email: [email protected].
Disclosure Summary: The author has nothing to disclose.
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