IL-13 suppresses TNF-induced activation of nuclear factor-kappa B, activation protein-1, and apoptosis.
IL-13 is known to suppress the production of inflammatory cytokines such as TNF. Whether IL-13 also modulates the biologic effects of TNF is not known. In the present report we examined the effect of IL-13 on TNF-induced activation of nuclear transcription factors NF-kappa B and activation protein-1 (AP-1) and apoptosis. Pretreatment of cells with IL-13 blocked TNF-induced NF-kappa B activation, nuclear translocation of p65 subunit, and degradation of I kappa B alpha. IL-13 also inhibited NF-kappa B activation by LPS, okadaic acid, H2O2, and ceramide. TNF-induced NF-kappa B-dependent gene transcription was also blocked by IL-13. TNF-induced activation of another nuclear transcription factor, AP-1, was suppressed by IL-13. The activation of N-terminal c-Jun kinase and mitogen-activated protein kinase kinase, implicated in the regulation of AP-1 and NF-kappa B, was also down-regulated by IL-13. TNF-mediated cytotoxicity and activation of caspase-3 were abolished by IL-13. The inhibitory effects of IL-13 on TNF were sensitive to H-7, neomycin, and wortmannin, suggesting that the pathway consisting of protein kinase C, phosphatidylinositol 3-kinase, and phospholipase C must be involved in IL-13 signaling. Thus, overall, these results demonstrate that IL-13 is a potent inhibitor of TNF-mediated activation of NF-kappa B, AP-1, and apoptosis, which may contribute to its previously described immunosuppressive and anti-inflammatory effects.
Manna
S K
SK
Department of Molecular Oncology, University of Texas M.D. Anderson Cancer Center, Houston 77030, USA.
Aggarwal
B B
BB
D017209:Apoptosis / Q000187:drug effects / Q000276:immunology*; D001692:Biological Transport / Q000187:drug effects / Q000276:immunology; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D053148:Caspase 3; D020169:Caspases; D003546:Cysteine Endopeptidases / Q000187:drug effects / Q000378:metabolism; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D003602:Cytotoxicity, Immunologic / Q000187:drug effects; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects / Q000276:immunology; D005786:Gene Expression Regulation / Q000187:drug effects / Q000276:immunology; D006801:Humans; D006861:Hydrogen Peroxide / Q000037:antagonists & inhibitors / Q000494:pharmacology; D020672:I-kappa B Proteins; D007166:Immunosuppressive Agents / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D018793:Interleukin-13 / Q000037:antagonists & inhibitors / Q000494:pharmacology* / Q000502:physiology; D048031:JNK Mitogen-Activated Protein Kinases; D008070:Lipopolysaccharides / Q000037:antagonists & inhibitors / Q000494:pharmacology; D020928:Mitogen-Activated Protein Kinases; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D019319:Okadaic Acid / Q000037:antagonists & inhibitors / Q000494:pharmacology; D010766:Phosphorylation; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology; D013755:Tetradecanoylphorbol Acetate / Q000037:antagonists & inhibitors / Q000494:pharmacology; D018808:Transcription Factor AP-1 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D051996:Transcription Factor RelA; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000494:pharmacology*
D015853:Cysteine Proteinase Inhibitors; D004268:DNA-Binding Proteins; D020672:I-kappa B Proteins; D007166:Immunosuppressive Agents; D018793:Interleukin-13; D008070:Lipopolysaccharides; D016328:NF-kappa B; C000606204:NFKBIA protein, human; D018808:Transcription Factor AP-1; D051996:Transcription Factor RelA; D014409:Tumor Necrosis Factor-alpha; D000072000:NF-KappaB Inhibitor alpha; D019319:Okadaic Acid; D006861:Hydrogen Peroxide; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; C505407:CASP3 protein, human; D053148:Caspase 3; D020169:Caspases; D003546:Cysteine Endopeptidases; D013755:Tetradecanoylphorbol Acetate