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 activates the release of hypothalamic CRH. Direct injections of IL-1 beta into the hypothalamic median eminence (ME), a site which lacks a blood-brain barrier, has been shown to rapidly induce ACTH secretion. Therefore, the ME is a likely site whereby circulating IL-1 beta can access the brain to stimulate CRH and, consequently, ACTH secretion. To further evaluate this hypothesis, an angular stereotaxic approach was developed 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 of [I-125]-IL-1 beta (100 nl delivered over 60 s) showed that 97% remained 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 the 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 were 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 after intra-ME IL-1 beta. Indomethacin, an inhibitor of prostaglandin (PG) synthesis, has been shown to block both the induction of CRH secretion by IL-1 beta from hypothalamic explants, as well as the ACTH response 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 dose of indomethacin (1 mg/kg i.v.) was administered 20 min before intra-ME IL-1 beta (25 ng). Finally, plasma ACTH was elevated in a dose-dependent 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 each was administered alone or in combination. Additivity of the response, 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 summary, the ACTH response to IL-1 beta delivered into the ME appears to be mediated by local prostaglandins.