Lipopolysaccharide‐induced interleukin‐10 in mice: role of endogenous tumor necrosis factor‐α

Publisher Website
Google Scholar
Abstract
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‐α (TNF‐α) with IL‐10. Neutralization of TNF‐α 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‐α) and, after a nadir at 6 h, a second increase between 8 and 12 h. Treatment of mice with neutralizing anti‐mouse TNF‐α 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‐γ (IFN‐γ) 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‐α revealed that the amount of transcripts in the liver correlated with circulating early and late IL‐10 levels. Our findings suggest that endogenous TNF‐α 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.