REGULATION OF INTERLEUKIN-1 RECEPTORS AND HYPOTHALAMIC-PITUITARY-ADRENAL AXIS BY LIPOPOLYSACCHARIDE TREATMENT IN THE MOUSE

We measured iodine-125-labeled recombinant human interleukin-la (I-125-IL-1 alpha) binding in the hippocampus, pituitary, liver, spleen and testis, and plasma adrenocorticotropic hormone (ACTH) and corticosterone levels after i.p. injection of various dose and treatment regimens of the bacterial endotoxin, lipopolysaccharide (LPS). Plasma ACTH and corticosterone levels were significantly increased at 2 h after acute administration of LPS (60 or 300 mu g/mouse). I-125-IL-1 alpha binding in all peripheral tissues examined was significantly and comparably decreased at 2 h after a single injection of 30 mu g or 300 mu g LPS/mouse. On the other hand, I-125-IL-1 alpha binding in hippocampus was significantly decreased only after high dose administration of LPS (300 mu g/mouse). In order to evaluate if activation of IL-1 in brain resulting in the observed decrease in I-125-IL-1 alpha binding may require more sustained exposure to endotoxin, we compared the effects of a single injection (60 mu g/mouse) and two injections of LPS (30 mu g/mouse each at 0 and 12 h). A single injection of LPS (60 mu g/mouse) decreased I-125-IL-1 alpha binding in the testis but not in the hippocampus, while two LPS injections (30 mu g/mouse each at 0 and 12 h) caused dramatic reductions in I-125-IL-1 alpha binding in both the hippocampus and testis. These data demonstrating differential effects of LPS treatment on the regulation of IL-1 receptors in the brain versus peripheral tissues and on ACTH and corticosterone secretion suggest that sites of action outside the blood-brain barrier may be important in regulating the effects of IL-1 on the hypothalamic-pituitary-adrenal axis.