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.
Mesh Terms:
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
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
J. Exp. Med.
Date: Apr. 03, 2000
PubMed ID: 10748240
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