Synergistic roles of interleukin-6, interleukin-1, and tumor necrosis factor in the adrenocorticotropin response to bacterial lipopolysaccharide in vivo.
Administration of lipopolysaccharide (LPS) results in activation of the hypothalamic-pituitary-adrenal axis. LPS induces the release of a number of proinflammatory cytokines, i.e. interleukin-1 (IL-1), IL-6, and tumor necrosis factor (TNF), which activate the hypothalamic-pituitary-adrenal axis as well and may mediate the effects of LPS. Variations in the kinetics of appearance of IL-1, TNF, and IL-6 after LPS challenge suggested that these cytokines may play different roles at different times. To elucidate the mutual dependence and contribution of individual cytokines in the course of LPS-induced ACTH release, we used blocking antibodies to IL-6, TNF, and the IL-1 receptor. Our results demonstrate that anti-IL-6 antibody abrogated ACTH induction throughout the course of the response both 2 and 4 h after LPS challenge. In contrast, anti-IL-1 receptor and anti-TNF antibody, given individually, blocked ACTH production at 4 h, but not at 2 h. Only combined administration of these two antibodies diminished, but did not eliminate, ACTH release at 2 h. This is the first demonstration that all three inflammatory cytokines are obligatory for LPS-induced elevation of plasma ACTH. In addition, these results suggest that IL-1, IL-6, and TNF play different roles in LPS-induced ACTH release.
Department of Experimental Hematology, Armed Forces Radiobiology Research Institute, Bethesda, Maryland 20889-5145.
R S
RS
Perlstein
M H
MH
Whitnall
J S
JS
Abrams
E H
EH
Mougey
R
R
Neta
D000324:Adrenocorticotropic Hormone / Q000097:blood / Q000378:metabolism*; D000818:Animals; D004347:Drug Interactions; D004926:Escherichia coli; D005260:Female; D006801:Humans; D007030:Hypothalamo-Hypophyseal System / Q000187:drug effects / Q000502:physiology; D007375:Interleukin-1 / Q000494:pharmacology*; D015850:Interleukin-6 / Q000494:pharmacology*; D007700:Kinetics; D008070:Lipopolysaccharides / Q000302:isolation & purification / Q000494:pharmacology*; D051379:Mice; D008809:Mice, Inbred C3H; D011994:Recombinant Proteins / Q000494:pharmacology; D012016:Reference Values; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
D007375:Interleukin-1; D015850:Interleukin-6; D008070:Lipopolysaccharides; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; D000324:Adrenocorticotropic Hormone