Effects of the IL-1 receptor antagonist on the IL-1- and endotoxin-induced activation of the HPA axis and cerebral biogenic amines in mice.

Endotoxin (lipopolysaccharide, LPS) and interleukin-1 (IL-1) are known to activate the hypothalamo-pituitary- adrenocortical (HPA) axis, as well as brain norepinephrine (NE) and indoleamine metabolism. Because LPS administration is known to induce the synthesis and secretion of IL-1, it has been proposed that IL-1 is the endogenous mediator of the response to LPS. This proposal has been tested using various antagonists of IL-1 with varied results. Therefore we have re-examined this question using a wide range of doses of the interleukin-1- receptor antagonist protein (IL-1ra) at various times after intraperitoneal LPS. The results indicate that IL-1ra at doses more than adequate to prevent responses to exogenously administered IL-1beta, failed to significantly attenuate the increases in plasma ACTH and corticosterone and the cerebral catecholamine and indoleamine responses induced by intraperitoneal LPS in mice. IL-1ra was also ineffective when plasma ACTH and corticosterone were measured at longer times after LPS, although some trends towards attenuations were occasionally observed at 4 or 6 h. The latter is consistent with the time course of IL-1 induction by LPS. Intracerebroventricular administration of IL-1ra attenuated the endocrine and neurochemical responses to intraperitoneal IL-1beta. However, intracerebroventricular IL-1ra failed to antagonize the HPA and neurochemical responses to intraperitoneal administration of LPS or to intravenous IL-1beta. In all of these experiments, there were very close parallels between the HPA and the neurochemical responses, especially that of NE. We conclude that IL-1 does not mediate the HPA or the neurochemical responses to intraperitoneal LPS, although it may contribute in a minor way to the late HPA responses. However, IL-1 within the CNS may contribute to the responses to intraperitoneal IL-1, but not to intraperitoneal LPS or intravenous IL-1. Copyright 1999 S. Karger AG, Basel