EFFECT OF IL-1 RECEPTOR ANTAGONIST AND ANTISERUM TO TNF-ALPHA ON LPS-INDUCED PLASMA ACTH AND CORTICOSTERONE RISE IN RATS

Using an antiserum against tumor necrosis factor (TNF)-alpha and an in terleukin (IL)-1 receptor antagonist, we studied putative roles of the se cytokines in mediating the endotoxin-induced elevation of plasma ad renocorticotropic hormone (ACTH) and corticosterone levels in freely m oving rats. Intravenous administration of Escherichia coli lipopolysac charide (LPS) increased plasma ACTH and corticosterone levels in a dos e-dependent manner. The plasma corticosterone reached to its highest l evel among a series of experiments after the administration of even th e smallest dose (0.03 mu g/kg) tested. Plasma ACTH and corticosterone levels in these rats were completely inhibited by the intravenous admi nistration of anti-murine TNF-alpha-rabbit antiserum (anti-TNFAS) afte r the administration of LPS but not by the intravenous administration of IL-1 receptor antagonist (IL-1RA). On the other hand, both recombin ant human IL-1RA and anti-TNFAS significantly inhibited plasma ACTH in crease stimulated with 10 mu g/kg LPS. These findings indicate that 1) when the plasma corticosterone increase induced by intravenous LPS re mains below its maximum, the effect is exclusively mediated by TNF-alp ha, and 2) when a larger amount of LPS is administered, both IL-1 beta and TNF-alpha participate at least in part in the hypothalamic-pituit ary-adrenal axis activation.