Reduced adrenal response to bacterial lipopolysaccharide in interleukin-6-deficient mice.
Administration of bacterial lipopolysaccharide (LPS) in rodents induces the release of pro-inflammatory cytokines [tumor necrosis factor (TNF), interleukin (IL)-1, IL-6] and of ACTH and corticosterone. IL-6 is probably an important cytokine in the interaction between the immune system and the hypothalamus-pituitary-adrenal (HPA) axis, but so far the role of IL-6 in lipopolysaccharide (LPS)-induced HPA activation has not been established unequivocally. We examined the effects of intraperitoneal administration of LPS (range 0.25-2000 pg/mouse) on plasma corticosterone, TNFalpha and IL-1alpha levels in IL-6-deficient (IL-6 -/-) and wildtype control (IL-6 +/+) mice. Plasma corticosterone levels increased within one hour in both mouse strains. The corticosterone response was significantly reduced in IL-6 -/- mice, but no differences in TNFalpha or in IL-1alpha plasma levels were found between the two strains. Next, we studied the involvement of IL-1alpha or TNFalpha in the responses to LPS in IL-6 -/- and IL-6 +/+ mice by infusion of recombinant human IL-1 receptor antagonist (IL-1ra), or by injection of anti-TNFalpha antibodies. Pretreatment with IL-1ra or with anti-TNFalpha did not affect the corticosterone response to LPS, neither in IL-6 -/-, nor in IL-6 +/+ mice. Our data suggest that in the stimulation of the HPA axis by LPS in mice blockade of either IL-1alpha or TNFalpha may be compensated for by other mediators. The reduced adrenal response after LPS administration found in IL-6 -/- mice indicates a distinct role for IL-6 in the activation of the HPA axis by LPS.
van Enckevort
F H
FH
Department of Endocrinology, University Medical Centre Nijmegen, The Netherlands.
Sweep
C G
CG
Span
P N
PN
Demacker
P N
PN
Hermsen
C C
CC
Hermus
A R
AR
D000311:Adrenal Glands / Q000187:drug effects*; D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D003345:Corticosterone / Q000097:blood; D016207:Cytokines / Q000097:blood; D006801:Humans; D053590:Interleukin 1 Receptor Antagonist Protein; D007375:Interleukin-1 / Q000494:pharmacology; D015850:Interleukin-6 / Q000172:deficiency* / Q000235:genetics; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008297:Male; D051379:Mice; D018345:Mice, Knockout / Q000235:genetics; D011994:Recombinant Proteins / Q000494:pharmacology; D012795:Sialoglycoproteins / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology / Q000502:physiology
D000911:Antibodies, Monoclonal; D016207:Cytokines; C507763:IL1RN protein, human; C507764:Il1rn protein, mouse; D053590:Interleukin 1 Receptor Antagonist Protein; D007375:Interleukin-1; D015850:Interleukin-6; D008070:Lipopolysaccharides; D011994:Recombinant Proteins; D012795:Sialoglycoproteins; D014409:Tumor Necrosis Factor-alpha; D003345:Corticosterone