The goal of this research is to gain a greater understanding of the mechanisms by which recombinant interleukin-1beta (rIL-1) regulates the secretion of adrenocorticotropic hormone (ACTH) and corticosterone. The central hypotheses of this proposal are that rIL-1 stimulates the hypothalamic -pituitary-adrenal axis by directly action on the pituitary and adrenal glands, indirectly though known ACTH secretagogues such as corticotropin-releasing hormone (CRH) and catecholamines and via other cytokines, such as recombinant interleukin-6 (rIL-6). The first aim tests the hypotheses that rIL-1 and rIL-6 modify ACTH release from the pituitary gland either directly or indirectly; to this end, ACTH levels will be measured in both primary rat pituitary gland cell cultures and in rats treated with these cytokines and CRH, or alpha- and beta-adrenergic agonists and antagonists. Second, we will test the hypotheses that rIL-1 and rIL-6 stimulate pro-opiomelanocortin (POMC) mRNA accumulation in the anterior pituitary gland and that glucocorticoids inhibit this response, demonstrating both that rIL-1 and rIL-6 elevate POMC mRNA levels and that prior treatment with dexamethasone inhibits this response. The interaction of these cytokines with CRH and catecholamines will be examined; agonists and antagonists will be used to mimic these responses. Third, by comparing changes in corticosterone concentration in adrenocortical cells treated with these cytokines and incubated in the presence or absence of ACTH or catecholamines, we will establish if rIL-1 and rIL-6 directly stimulate the release of corticosterone from the adrenal cortex. These cytokine effects will also be demonstrated in adrenal slices and in vivo. The information obtained from these experiments will determine the role of rIL-1 and rIL-6 in activating the HPA axis: specifically, the site(s) of cytokine action, and the mechanism(s) of their activation. This research will aide in the development of methods of treating infectious and autoimmune diseases, tumors and cancers, as well as the neuroendocrine, psychological and other disorders that result when interactions between the endocrine and immune systems are not controlled.