Neurokinin B: a new player in immune/inflammatory stress-mediated suppression of reproduction.

Abstract

Both 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 increases 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