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.
Pubmed ID: 10748240 RIS Download
Animals | Cells, Cultured | DNA-Binding Proteins | Enzyme Activation | Humans | I-kappa B Kinase | I-kappa B Proteins | Intercellular Adhesion Molecule-1 | Interleukin-17 | Interleukin-6 | Mice | Mice, Knockout | Mitogen-Activated Protein Kinase 8 | Mitogen-Activated Protein Kinases | NF-kappa B | Protein-Serine-Threonine Kinases | Proteins | Receptors, Interleukin | Receptors, Interleukin-17 | Receptors, Tumor Necrosis Factor | Recombinant Proteins | Signal Transduction | TNF Receptor-Associated Factor 6