Requirement of tumor necrosis factor receptor-associated factor (TRAF)6 in interleukin 17 signal transduction.
Signaling through its widely distributed cell surface receptor, interleukin (IL)-17 enhances the transcription of genes encoding proinflammatory molecules. Although it has been well documented that IL-17 activates the transcription factor nuclear factor (NF)-kappaB and c-Jun NH(2)-terminal kinase (JNK), the upstream signaling events are largely unknown. Here we report the requirement of tumor necrosis factor receptor-associated factor (TRAF)6 in IL-17-induced NF-kappaB and JNK activation. In embryonic fibroblasts (EFs) derived from TRAF6 knockout mice, IL-17 failed to activate the IkappaB kinases (IKKs) and JNK. Consequently, IL-17-induced IL-6 and intercellular adhesion molecule 1 expression in the TRAF6-deficient cells was abolished. Lack of TRAF6 appeared to be the sole defect responsible for the observed failure to respond to IL-17, because transient transfection of TRAF6 expression plasmid into the TRAF6-deficient cells restored IL-17-induced NF-kappaB activation in a luciferase reporter assay. Furthermore, the levels of IL-17 receptor (IL-17R) on the TRAF6-deficient EFs were comparable to those on the wild-type control cells. Defect in IL-17 response was not observed in TRAF2-deficient EFs. Moreover, when TRAF6 and IL-17R were coexpressed in 293 cells, TRAF6 coimmunoprecipitated with IL-17R. Together, these results indicate that TRAF6, but not TRAF2, is a crucial component in the IL-17 signaling pathway leading to proinflammatory responses.
Schwandner
R
R
Tularik Incorporated, South San Francisco, California 94080, USA.
Yamaguchi
K
K
Cao
Z
Z
D000818:Animals; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000378:metabolism; D004789:Enzyme Activation; D006801:Humans; D051550:I-kappa B Kinase; D020672:I-kappa B Proteins; D018799:Intercellular Adhesion Molecule-1 / Q000096:biosynthesis; D020381:Interleukin-17 / Q000378:metabolism* / Q000494:pharmacology; D015850:Interleukin-6 / Q000096:biosynthesis; D051379:Mice; D018345:Mice, Knockout; D048055:Mitogen-Activated Protein Kinase 8; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011506:Proteins / Q000235:genetics / Q000378:metabolism*; D018123:Receptors, Interleukin / Q000378:metabolism; D053722:Receptors, Interleukin-17; D018124:Receptors, Tumor Necrosis Factor / Q000378:metabolism*; D011994:Recombinant Proteins / Q000378:metabolism; D015398:Signal Transduction; D048029:TNF Receptor-Associated Factor 6
D004268:DNA-Binding Proteins; C083487:I kappa B beta protein; D020672:I-kappa B Proteins; C109985:IL17RA protein, human; C491673:Il17ra protein, mouse; D020381:Interleukin-17; D015850:Interleukin-6; D016328:NF-kappa B; C000606204:NFKBIA protein, human; C000606205:Nfkbia protein, mouse; D011506:Proteins; D018123:Receptors, Interleukin; D053722:Receptors, Interleukin-17; D018124:Receptors, Tumor Necrosis Factor; D011994:Recombinant Proteins; D048029:TNF Receptor-Associated Factor 6; D018799:Intercellular Adhesion Molecule-1; D000072000:NF-KappaB Inhibitor alpha; D017346:Protein Serine-Threonine Kinases; C496559:CHUK protein, human; C496564:Chuk protein, mouse; D051550:I-kappa B Kinase; C496560:IKBKB protein, human; C496565:IKBKE protein, human; C496562:Ikbkb protein, mouse; C496566:Ikbke protein, mouse; D048055:Mitogen-Activated Protein Kinase 8; D020928:Mitogen-Activated Protein Kinases