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IL-10 is a potent anti-inflammatory cytokine and inhibitor of TNF-alpha production. The molecular pathways by which IL-10 inhibits TNF-alpha production are obscure, with diverse mechanisms having been published. In this study, a new approach has been taken for the study of human cells. Adenovirus was used to deliver TNF-alpha promoter-based luciferase reporter genes to primary human monocytic cells. The reporter genes were highly responsive to macrophage activation and appeared to mirror the behavior of the endogenous TNF-alpha gene. When added, either with or after the stimulus, IL-10 required the 3' untranslated region of the TNF-alpha gene to inhibit luciferase mRNA and protein expression, indicating a posttranscriptional mechanism. However, if macrophages were incubated with IL-10 before activation, inhibition of gene expression was also mediated by the 5' promoter, suggesting a transcriptional mechanism. To our knowledge, this is the first time that a dual mechanism for IL-10 function has been demonstrated. Studies to elucidate the mechanisms underlying the inhibition of TNF-alpha production addressed the effect of IL-10 on the activation of p38 mitogen-activated protein kinase and NF-kappaB. However, these studies could demonstrate no requirement for the inhibition of p38 mitogen-activated protein kinase or NF-kappaB activation as potential mechanisms. Overall, these results may explain the diversity previously ascribed to the complex mechanisms of IL-10 anti-inflammatory activity.

Type

Journal article

Journal

J Immunol

Publication Date

15/05/2002

Volume

168

Pages

4837 - 4845

Keywords

3' Untranslated Regions, 5' Untranslated Regions, Adenoviridae, Cells, Cultured, Enzyme Activation, Enzyme Inhibitors, Gene Expression Regulation, Genes, Reporter, Humans, Immunosuppressive Agents, Interleukin-10, Lipopolysaccharides, Macrophages, Mitogen-Activated Protein Kinases, NF-kappa B, Promoter Regions, Genetic, RNA Stability, RNA, Messenger, Tumor Necrosis Factor-alpha, Zymosan, p38 Mitogen-Activated Protein Kinases