ENDOTOXIN-INDUCED CORTICOTROPIN-RELEASING HORMONE GENE-EXPRESSION IN THE HYPOTHALAMIC PARAVENTRICULAR NUCLEUS IS MEDIATED CENTRALLY BY INTERLEUKIN-1

In the acute phase of bacterial infection, a variety of cytokines, inc luding interluekin-I (IL-1), are elicited by bacterial endotoxin in bo th the periphery and the central nervous system. Bacterial endotoxin h as been previously reported to profoundly activate the hypothalamic-pi tuitary-adrenal axis, resulting in elevated glucocorticoid secretion t hat may serve an important role as part of the inhibitory feedback mec hanisms on the activated immune system. To determine whether IL-1 acts within the brain to mediate endotoxin-induced CRH gene expression in the hypothalamic paraventricular nucleus (PVN), we studied the effect of administering the human IL-1 receptor antagonist (IL-1ra) into the brain, a competitive inhibitor of IL-1, on CRH gene expression in the PVN after systemic lipopolyaaccharide (LPS) treatment. Eight hours aft er the ip administration of LPS, the paraventricular CRH mRNA content was elevated 3- to 4-fold (P < 0.01) compared to the control value, an d this elevation could be completely abolished by central IL-1ra pretr eatment (P < 0.05 compared to LPS-treated group; P > 0.05 compared to controls). In contrast, systemic IL-1ra administration did not inhibit endotoxin-induced CRH gene expression in the PVN. These studies demon strate that LPS stimulates hypothalamic CRH by a mechanism that involv es the action of IL-1 within the central nervous system and may procee d independently of peripheral actions of IL-1 circulating in the blood stream.