A study on the cytokine regulation of the hypothalamo-pituitary-adrenal system in the rat

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A growing body of evidence suggests that various cytokines produced by activated immune cells during bacterial infection are able to stimulate the hypothalamo-pituitary-adrenal (HPA) axis in humams and animals. However, there are a great number of as yet unanswered problems in this area of research. In this study, we conducted a couple of experiments in rats to have a better understanding of the cytokine regulation of the HPA axis in this species. Specific experiments performed in the present study and implications obtained from each of them are summarized below.(1)Utilizing the technique of push-pull perfusion (PPP) of the brain, we examined the site of action of interleukin (IL) -1beta within the corticotropinreleasing hormone (CRH) neuronal system. We obtained the data suggesting that IL-1beta may act on both the paraventricular nucleus (PVN,the site where CRH neuronal cell bodies are localized) and the median eminence (ME,the site where axonal fibers of CRH neurons are terminated). … More It was also suggested that not only CRH but arginine vasopressin (AVP) may mediate the IL-1beta stimulation of ACTH secretion.(2)Utilizing the PPP method again, we examined the alleged significant role of prostaglandin (PG) E_2 in the IL-1beta stimulation of ACTH secretion. After an intravenous administration of IL-1beta, a significant rise in PGE_2 was observed in the PVN but not in the ME or the preoptic area of the hypothalamus.The increase in PGE_2 in the PVN was in synchrony with the rise in CRH and AVP levels in the same hypothalamic area. These results strongly suggest that PGE_2 in the PVN may be a trigger for the activation of CRH neurons, which then leads to ACTH secretion.Utilizing the technique of immunoneutralization of brain neuropeptides, we examined if other ACTH secretagogues such as oxytocin (OT), angiotensin II(A II), and cholecystokinin (CCK)-8, are also involved in the ACTH response induced by intracerebroventricular (icv) administration of IL-1beta. Through examining the effects of icv injection of antisera against these peptides, we obtained the data suggesting that A II,but not OT or CCK-8, may mediate the IL-1beta stimulation of ACTH secretion. In addition, utilizing the same technique, we examined whether CRH and AVP contribute to the ACTH response induced by icv injection of IL-6 and tumor necrosis factor (TNF)-alpha. It was suggested that IL-6-induced ACTH response may be mediated by both CRH and AVP, whereas the ACTH response to TNF-alpha only via CRH. Less