The long-term objective of this application is to understand how the immune and neuroendocrine systems interact when activated by stress or infection in the human and nonhuman primate.
The specific aims will focus on the inflammatory cytokines (IL-1, IL-6, TNFalpha) and mechanisms of hypothalamic-pituitary-adrenal (HPA) activation with an emphasis in the role of gonadal steroids in modulating cytokine and neuroendocrine responses. Previous studies in the investigators' laboratory have established that intracerebroventricular (icv) IL-1 stimulates the HPA axis in the monkey and that this affect can be blocked by corticotropin-releasing hormone (CRH) antagonism. Preliminary studies in the monkey indicate that icv IL-1 also causes profound suppression of lymphocyte function and marked stimulation of Il-6 secretion into peripheral blood, possibly by a CRH dependent mechanism. In this application, using rhesus monkeys, IL-1 CRH interactions in the brain and their modulation by gonadal steroids will be examined in vivo with respect to mechanisms of HPA activation and regulation of peripheral lymphocyte and cytokine responses. A major focus will be to characterize the endogenous cytokine and neuroendocrine responses caused by a physiological inflammatory challenge in the human. Low doses of a highly purified endotoxin preparation will be use to stimulate cytokine release and to characterize the HPA response in women in the presence and absence of gonadal steroids. The CNS cytokines and CRH into CSF after stimulation with endotoxin will be measured in monkeys with chronic CSF catheters, and specific cytokine antagonists will be infused icv to establish a role for the endogenous cytokines within the brain in neuroendocrine regulation. The ability of gonadal steroids to modulate central cytokine release will also be studied. These studies may relate to a wide range of human diseases since cytokine interactions in brain triggered by injury or infection may be associated with neurodegeneration and immunosuppression. If sex steroids restrain these cytokine-neuropeptide interactions, such pathology could be exacerbated when sex steroid levels fall. These studies should thus have direct relevance to the important clinical issue of sex steroid replacement during menopause and in other hypogonadal states.
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