In the mouse, the activation of the hypothalamic-pituitary-adrenal axis by a lipopolysaccharide (endotoxin) is mediated through interleukin-1.
The mechanisms through which endotoxin stimulates the hypothalamic-pituitary-adrenal axis are not well understood. In the studies reported here we tested the hypothesis that endotoxin increases plasma ACTH levels by releasing interleukin-1 (Il-1). Two experimental tools reported to interfere with the biological activity of IL-1 were used: antibodies directed against IL-1 receptors and alpha MSH. In a first series of experiments, adult male mice were injected with a lipopolysaccharide (LPS; 25 micrograms), antibodies against IL-1 receptor, alpha MSH (1-30 micrograms), or LPS and either IL-1 antibodies or alpha MSH. All treatments were administered ip. The endotoxin LPS caused a marked increase in plasma ACTH levels, measured 6 h later. Both alpha MSH and the Il-1 receptor antibodies, while having no effect by themselves, significantly (P less than or equal to 0.01) blocked LPS-induced ACTH release. In a second series of experiments, mice were injected ip with 500 ng recombinant human (rh) Il-1 alpha or 100 ng rhIl-1 beta in the presence or absence of alpha MSH (1-30 micrograms, ip). While not altering ACTH secretion induced by rhIl-1 alpha, 10-30 micrograms alpha MSH significantly (P less than or equal to 0.01) interfered with the effect of rhIl-1 beta. These results suggest 1) that endotoxin activates the hypothalamic-pituitary-adrenal axis through a mechanism involving the activation of interleukin-1 receptors; and 2) that the effect of rhIl-1 beta, but not -alpha, on ACTH secretion by the mouse can be partially blocked by alpha MSH.
Rivier
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C
Clayton Foundation Laboratories for Peptide Biology, Salk Institute, La Jolla, California 92037.
Chizzonite
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Vale
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D000311:Adrenal Glands / Q000502:physiology*; D000324:Adrenocorticotropic Hormone / Q000097:blood; D000818:Animals; D004347:Drug Interactions; D004731:Endotoxins / Q000494:pharmacology*; D004926:Escherichia coli; D007031:Hypothalamus / Q000502:physiology*; D007116:Immunization, Passive; D007375:Interleukin-1 / Q000502:physiology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D010902:Pituitary Gland / Q000502:physiology*; D011971:Receptors, Immunologic / Q000276:immunology / Q000502:physiology; D017472:Receptors, Interleukin-1; D011994:Recombinant Proteins / Q000494:pharmacology; D000521:alpha-MSH / Q000494:pharmacology
D004731:Endotoxins; D007375:Interleukin-1; D011971:Receptors, Immunologic; D017472:Receptors, Interleukin-1; D011994:Recombinant Proteins; D000521:alpha-MSH; D000324:Adrenocorticotropic Hormone