Lipopolysaccharide-induced interleukin-10 in mice: role of endogenous tumor necrosis factor-alpha.
Interleukin (IL)-10 is known to protect mice against the lethal effects of lipopolysaccharides (LPS) and is considered to be an anti-inflammatory cytokine which suppresses the production of pro-inflammatory cytokines. We have examined the interactions of the pro-inflammatory cytokine tumor necrosis factor-alpha (TNF-alpha) with IL-10. Neutralization of TNF-alpha in murine bone marrow-derived macrophages resulted in a significant reduction of LPS-inducible IL-10 production. In mice, injection of 5 mg/kg LPS induced circulating IL-10 with a biphasic time course exhibiting an early peak 1.5 h after challenge (synchronous with TNF-alpha) and, after a nadir at 6 h, a second increase between 8 and 12 h. Treatment of mice with neutralizing anti-mouse TNF-alpha antiserum significantly increased LPS-induced IL-10 plasma levels between 1.5 and 6 h but diminished those at 12 h, while circulating IL-6, interferon-gamma (IFN-gamma) and granulocyte colony-stimulating factor (G-CSF) concentrations were attenuated overall, without a biphasic response. Analysis of LPS-induced IL-10 mRNA expression in different tissues 1 h and 8 h after LPS or LPS plus anti-TNF-alpha revealed that the amount of transcripts in the liver correlated with circulating early and late IL-10 levels. Our findings suggest that endogenous TNF-alpha down-regulates the early and up-regulates the late LPS-induced IL-10 synthesis in vivo and that the liver is the major source of circulating IL-10 after stimulation with LPS.
Barsig
J
J
Biochemical Pharmacology, Faculty of Biology, University of Konstanz, Germany.
Küsters
S
S
Vogt
K
K
Volk
H D
HD
Tiegs
G
G
Wendel
A
A
D000818:Animals; D001427:Bacterial Toxins / Q000494:pharmacology; D001854:Bone Marrow Cells; D002478:Cells, Cultured; D004731:Endotoxins / Q000494:pharmacology; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects*; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000494:pharmacology; D007153:Immunologic Deficiency Syndromes / Q000276:immunology / Q000503:physiopathology; D007371:Interferon-gamma / Q000096:biosynthesis; D016753:Interleukin-10 / Q000096:biosynthesis* / Q000235:genetics; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008264:Macrophages / Q000187:drug effects* / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D016513:Mice, SCID; D009928:Organ Specificity; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000502:physiology*
D001427:Bacterial Toxins; D004731:Endotoxins; D008070:Lipopolysaccharides; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; C027952:salmonella toxin; D016753:Interleukin-10; D007371:Interferon-gamma; D016178:Granulocyte-Macrophage Colony-Stimulating Factor