The role of interleukin-1 and tumor necrosis factor alpha in the neurochemical and neuroendocrine responses to endotoxin.
Both interleukin-1 (IL-1) and endotoxin (lipopolysaccharide, LPS) are potent activators of the hypothalamo-pituitary-adrenal (HPA) axis, and they also increase cerebral norepinephrine metabolism and tryptophan. Injections of cause macrophages to synthesize and release various cytokines, including IL-1 and tumor necrosis factor alpha (TNF alpha). The hypothesis that macrophage production of IL-1 mediates the HPA-activating effect of LPS was tested in mice using the IL-1-receptor antagonist protein (IRAP). Administration of IRAP largely prevented the effects of IL-1 alpha or IL-1 beta on the elevation of plasma corticosterone and the concomitant increase in hypothalamic norepinephrine metabolism, but failed to alter the responses to LPS. IRAP did not prevent the increases in brain tryptophan that occurred after treatment with IL-1 or LPS. Recombinant human TNF alpha, TNF beta, IL-6, and interferon-alpha injected intraperitoneally failed to activate the HPA axis, but mouse TNF alpha was effective by this route, and human TNF alpha, TNF beta, and IL-6 were effective intravenously. None of these cytokines was as potent as IL-1. Pretreatment with an antibody specific for mouse TNF alpha, either alone or in combination with IRAP, also failed to prevent the elevation of plasma corticosterone by LPS. Thus, either IL-1 and TNF alpha are not involved in the HPA and noradrenergic responses to LPS, or there are alternative (redundant) pathways by which LPS can activate the HPA axis.
Dunn
A J
AJ
Department of Pharmacology and Therapeutics, Louisiana State University Medical Center, Shreveport 71130-3932.
D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D003345:Corticosterone / Q000097:blood; D004926:Escherichia coli; D006801:Humans; D007031:Hypothalamus / Q000187:drug effects / Q000378:metabolism*; D053590:Interleukin 1 Receptor Antagonist Protein; D007375:Interleukin-1 / Q000494:pharmacology* / Q000502:physiology; D015850:Interleukin-6 / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008233:Lymphotoxin-alpha / Q000494:pharmacology; D008297:Male; D008734:Methoxyhydroxyphenylglycol / Q000378:metabolism; D051379:Mice; D008815:Mice, Inbred Strains; D009638:Norepinephrine / Q000378:metabolism; D011994:Recombinant Proteins / Q000494:pharmacology; D012795:Sialoglycoproteins / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology / Q000494:pharmacology* / Q000502:physiology
D000906:Antibodies; C507763:IL1RN protein, human; C507764:Il1rn protein, mouse; D053590:Interleukin 1 Receptor Antagonist Protein; D007375:Interleukin-1; D015850:Interleukin-6; D008070:Lipopolysaccharides; D008233:Lymphotoxin-alpha; D011994:Recombinant Proteins; D012795:Sialoglycoproteins; D014409:Tumor Necrosis Factor-alpha; D008734:Methoxyhydroxyphenylglycol; D003345:Corticosterone; D009638:Norepinephrine