PROSTAGLANDINS MEDIATE THE ACTH RESPONSE TO INTERLEUKIN-1-BETA INSTILLED INTO THE HYPOTHALAMIC MEDIAN-EMINENCE

Interleukin-1 beta (IL-1 beta) is a potent ACTH secretagogue which act ivates the release of hypothalamic CRH. Direct injections of IL-1 beta into the hypothalamic median eminence (ME), a site which lacks a bloo d-brain barrier, has been shown to rapidly induce ACTH secretion. Ther efore, the ME is a likely site whereby circulating IL-1 beta can acces s the brain to stimulate CRH and, consequently, ACTH secretion. To fur ther evaluate this hypothesis, an angular stereotaxic approach was dev eloped to localize the spread of IL-1 beta to the ME and to optimally separate the injectate from the hypothalamic paraventricular nucleus ( PVN), another proposed site of IL-1 action. Studies of the diffusion o f [I-125]-IL-1 beta (100 nl delivered over 60 s) showed that 97% remai ned within 200 mu m of the ventral surface of the hypothalamus and 87% was contained within a radius of 550 mu m of the injection site in th e sagittal plane. Additional rats received recombinant human IL-1 beta (0.2-25.0 ng in 100 nl) into the ME (intra-ME). Plasma ACTH levels we re significantly elevated by a much lower dose (0.5 ng, p < 0.001) of IL-1 beta than that previously reported. Responses appeared to be dose -dependent and ACTH was maximally stimulated by 2.0 ng IL-1 beta. Also , immunocytochemically labelled CRH in the ME was markedly depleted af ter intra-ME IL-1 beta. Indomethacin, an inhibitor of prostaglandin (P G) synthesis, has been shown to block both the induction of CRH secret ion by IL-1 beta from hypothalamic explants, as well as the ACTH respo nse to intravenous IL-1 beta. Thus, indomethacin was used to determine whether PGs are mediators of the ACTH response to IL-1 beta delivered into the ME. The ACTH response was abolished (p < 0.005) when a low d ose of indomethacin (1 mg/kg i.v.) was administered 20 min before intr a-ME IL-1 beta (25 ng). Finally, plasma ACTH was elevated in a dose-de pendent manner by the intra-ME administration of PGs. The hierarchy of ACTH responses to PGE(2) were: CSF < 0.5 mu g (p < 0.001) = 2.0 mu g < 4.0 mu g (p < 0.05). Responses to PGF(2 alpha), were: CSF < 0.5 mu g (p < 0.001) < 2.0 mu g (p < 0.05) = 4.0 mu g. Since these PGs appear to activate different second-messenger systems, a submaximal dose of e ach was administered alone or in combination. Additivity of the respon se, rather than synergy, was evident, since the overall ACTH level in response to the combination of PGE(2) and PGF(2 alpha), (0.5 mu g each ) was no greater than the sum of the two separate treatments. In summa ry, the ACTH response to IL-1 beta delivered into the ME appears to be mediated by local prostaglandins.