CENTRALLY INJECTED INTERLEUKIN-1-BETA INHIBITS THE HYPOTHALAMIC LHRH SECRETION AND CIRCULATING LH LEVELS VIA PROSTAGLANDINS IN RATS

Intracerebroventricular (icv) infusion of interleukin-1beta (IL-1beta) significantly lowers plasma LH levels in castrated male rats, and interferes with LHRH release into the median eminence of proestrus female rats. We have investigated the potential role of arachidonic acid metabolites in mediating these inhibitory effects, by administering indomethacin (INDO, a cyclooxygenase inhibitor) or nor- dihydroguaiaretic acid (NDGA, a lipoxygenase inhibitor) 15 min prior to injection of the cytokine. While not measurably altering basal LH or LHRH secretion in castrated or proestrus rats, respectively, INDO completely reversed the action of IL-1beta on the secretion of these 2 hormones. In contrast, NDGA did not alter IL-1-induced decreases in LH release. The peripheral administration of endotoxin (LPS) also interferes with LH release. Because the iv injection of IL-1 does not alter LH secretion, this effect is believed to be at least in part mediated by increased synthesis of cytokines within the CNS. We observed that in contrast to results obtained in rats injected with IL-1 icv, INDO did not reverse the inhibitory action of LPS. Our results thus suggest either that central IL-1 is not the primary modulator of LPS-induced decrease in LH values, or that pathways other than those involving arachidonic acid are important. In conclusion, we have shown that: 1) the ability of IL-1beta to decrease the activity of the HPG axis is dependent on arachidonic acid metabolites (in particular those formed through the eicosanoid cyclooxygenase route); 2) under circumstances of increased IL-1beta levels within the CNS, prostaglandins exert an overall inhibitory effect on the hypothalamic LHRH secretion and plasma LH levels in rats.