The cytokine interleukin-1 (IL-1) alters a variety of immune, central nervous system, and neuroendocrine activities characteristic of an integrator of the brain-endocrine-immune response to stress. In an attempt to define the regulation of IL-1 and IL-1 receptors in the mouse brain-endocrine-immune axis, we measured tissue levels of IL-1 beta using an enzyme-linked immunosorbent assay and iodine-125-labeled recombinant human IL-1 alpha ([125I]IL-1 alpha) binding in hippocampus, hypothalamus, pituitary, epididymus, testis, and spleen after ip injection of the bacterial endotoxin lipopolysaccharide (LPS). Basal IL-1 beta levels were detectable in all of the tissues examined. IL-1 beta levels were dramatically increased in the peripheral tissues (pituitary, testis, and spleen) 2-6 h after a single LPS injection; however, no significant changes were observed in the brain (hippocampus and hypothalamus). [125I]IL-1 alpha binding was decreased in the spleen, but was unchanged in the hippocampus and testis after a single LPS injection. To determine whether activation of IL-1 in brain may require more sustained exposure to endotoxin, we examined the effects of two injections of LPS at 0 and 12 h. After two LPS injections (0 and 12 h), significant increases in IL-1 beta concentrations were noted in the hippocampus, hypothalamus, spleen, testis and epididymus; [125I]IL-1 alpha binding using quantitative autoradiography was significantly decreased in all tissues, including the pituitary gland. Saturation studies in whole testis homogenates demonstrated that the LPS-induced decrease in [125I]IL-1 alpha binding was primarily due to a decrease in the density of IL-1 receptors. These data demonstrate that LPS treatment results in elevated circulating and/or tissue levels of IL-1, which, in turn, down-regulates IL-1 receptors in the brain-endocrine-immune axis.