Lipopolysaccharides (LPS) activate both the immune and the stress response system. The effects of these bacterial endotoxins involve the release of interleukin 1 (IL1) and other cytokines, which in turn stimulate the hypothalamic-pituitary-adrenal (HP A) axis. We studied the binding properties of the corticosteroid receptor system, which mediates feedback inhibition of the HPA axis, in two brain areas and in the pituitary gland in rats treated with LPS and recombinant murine IL1β. The binding properties of the corticosteroid receptors were determined by Scatchard plot analyses of in vitro cytosolic binding of the tritiated mineralocorticoid receptor (MR) radioligand aldosterone and the tritiated glucocorticoid receptor (GR) ligand RU28362. Tissues were collected 48 h after administration of LPS, including a 24-hour period for depletion of endogenous corticosterone. LPS teatment increased the K_d of [³H]aldosterone of the hippocampal MR 4.3-fold and the apparent maximum binding capacity (B_max) of [³H]aldosterone by 65% during a time interval when the concentration of corticosterone, the endogenous ligand of both hippocampal MR and GR, was elevated in the intact rat. Thereafter, MR binding properties were not different from vehicle-injected controls, at 96 h, when in intact animals the enhanced HPA activity subsided. GRs, determined by binding of [³H]RU28362, were not affected by LPS. IL1 evoked a 2.7-fold increase in the K_d of the hippocampal MR and a 57% increase in B_max 3 h after injection into the lateral cerebral ventricle. An autoradiographic procedure revealed that the same treatment with IL1 reduced the retention of the tritiated endogenous MR ligand corticosterone by 40-60% in all pyramidal cell layers and in the dentate gyrus of the hippocampus, when a tracer dose of the steroid was administered that gives rise to a concentration around the K_d of the MR. This reduced in vivo retention of corticosterone is predicted in view of the reduced affinity of hippocampal MRs. The data are consistent with the hypothesis that an impaired feedback of the HPA axis via deficient hippocampal MRs contributes to stimulate corticosterone secretion from the adrenals during infection.

The role of endogenous corticoids in fever responses caused by recombinant murine interleukin (IL)-1β and IL-6 was studied in adult male Wistar rats. Adrenalectomy diminished the development of fever after intracerebroven-tricular (icv) injection of these ILs and lowered body temperature. Intraperitoneal administration of the same doses of ILs did not produce fever in intact animals or hypothermia in adrenalectomized rats, thus suggesting a central site of action of IL-1β and IL-6 in these experiments. Chronic replacement with moderate doses of corticosterone restored the fever response in adrenalectomized animals in response to icv administration of IL-1β but only partially reversed the fever caused by IL-6. Adrenalectomized animals acutely treated with corticosterone and thereafter with either IL-1β or IL-6 developed fever more rapidly than did chronically corticosterone-treated animals. In intact animals corticosterone blocked the fever response to icv injected IL-1β. We propose that in the rat corticosterone acts in a bimodal manner on body temperature; it exerts a permissive central effect on the fever response and limits the production of inflammatory mediators in the brain. Conversely, higher corticosterone doses probably reduce the magnitude of the fever response.