ENDOTOXIN AND INTERLEUKIN-1 DECREASE THE AFFINITY OF HIPPOCAMPAL MINERALOCORTICOID (TYPE-I) RECEPTOR IN PARALLEL TO ACTIVATION OF THE HYPOTHALAMIC-PITUITARY-ADRENAL AXIS

Lipopolysaccharides (LPS) activate both the immune and the stress resp onse system. The effects of these bacterial endotoxins involve the rel ease of interleukin 1 (IL1) and other cytokines, which in turn stimula te the hypothalamic-pituitary-adrenal (HPA) axis. We studied the bindi ng properties of the corticosteroid receptor system, which mediates fe edback inhibition of the HPA axis, in two brain areas and in the pitui tary gland in rats treated with LPS and recombinant murine IL1 beta. T he binding properties of the corticosteroid receptors were determined by Scatchard plot analyses of in vitro cytosolic binding of the tritia ted mineralocorticoid receptor (MR) radioligand aldosterone and the tr itiated glucocorticoid receptor (GR) ligand RU28362. Tissues were coll ected 48 h after administration of LPS, including a 24-hour period for depletion of endogenous corticosterone. LPS treatment increased the K -d of [H-3]aldosterone of the hippocampal MR 4.3-fold and the apparent maximum binding capacity (B-max) of [H-3]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-inj ected controls, at 96 h, when in intact animals the enhanced HPA activ ity subsided. GRs, determined by binding of [H-3]RU28362, were not aff ected by LPS. IL1 evoked a 2.7-fold increase in the K-d of the hippoca mpal MR and a 57% increase in B-max 3 h after injection into the later al cerebral ventricle. An autoradiographic procedure revealed that the same treatment with IL1 reduced the retention of the tritiated endoge nous MR ligand corticosterone by 40-60% in all pyramidal cell layers a nd 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 pr edicted in view of the reduced affinity of hippocampal MRs. The data a re consistent with the hypothesis that an impaired feedback of the HPA axis via deficient hippocampal MRs contributes to stimulate corticost erone secretion from the adrenals during infection.