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^a Tularik Incorporated, South San Francisco, California 94080
Tularik Inc., Two Corporate Dr., South San Francisco, CA 94080.650-825-7400650-825-7481

cao{at}tularik.com

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)-B and c-Jun NH₂-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-B and JNK activation. In embryonic fibroblasts (EFs) derived from TRAF6 knockout mice, IL-17 failed to activate the IB 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-B 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.

Key Words: cytokines • inflammation • signaling • kinases • transcription

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• Liu, C., Qian, W., Qian, Y., Giltiay, N. V., Lu, Y., Swaidani, S., Misra, S., Deng, L., Chen, Z. J., Li, X. (2009). Act1, a U-box E3 Ubiquitin Ligase for IL-17 Signaling. Sci Signal 2: ra63-ra63 [Abstract] [Full Text]  
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• Brand, S (2009). Crohn's disease: Th1, Th17 or both? The change of a paradigm: new immunological and genetic insights implicate Th17 cells in the pathogenesis of Crohn's disease. Gut 58: 1152-1167 [Abstract] [Full Text]  
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• Yang, Y. J., Chen, W., Carrigan, S. O., Chen, W.-M., Roth, K., Akiyama, T., Inoue, J.-i., Marshall, J. S., Berman, J. N., Lin, T.-J. (2008). TRAF6 Specifically Contributes to Fc{epsilon}RI-mediated Cytokine Production but Not Mast Cell Degranulation. J. Biol. Chem. 283: 32110-32118 [Abstract] [Full Text]  
• Sakai, A., Sugawara, Y., Kuroishi, T., Sasano, T., Sugawara, S. (2008). Identification of IL-18 and Th17 Cells in Salivary Glands of Patients with Sjogren's Syndrome, and Amplification of IL-17-Mediated Secretion of Inflammatory Cytokines from Salivary Gland Cells by IL-18. J. Immunol. 181: 2898-2906 [Abstract] [Full Text]  
• Paunovic, V., Carroll, H. P., Vandenbroeck, K., Gadina, M. (2008). Signalling, inflammation and arthritis: Crossed signals: the role of interleukin (IL)-12, -17, -23 and -27 in autoimmunity. Rheumatology (Oxford) 47: 771-776 [Abstract] [Full Text]  
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• Linden, A. (2007). A Role for the Cytoplasmic Adaptor Protein Act1 in Mediating IL-17 Signaling. Sci Signal 2007: re4-re4 [Abstract] [Full Text]  
• Maitra, A., Shen, F., Hanel, W., Mossman, K., Tocker, J., Swart, D., Gaffen, S. L. (2007). Distinct functional motifs within the IL-17 receptor regulate signal transduction and target gene expression. Proc. Natl. Acad. Sci. USA 104: 7506-7511 [Abstract] [Full Text]  
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• Chang, S. H., Park, H., Dong, C. (2006). Act1 Adaptor Protein Is an Immediate and Essential Signaling Component of Interleukin-17 Receptor. J. Biol. Chem. 281: 35603-35607 [Abstract] [Full Text]  
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• Shimada, M., Andoh, A., Hata, K., Tasaki, K., Araki, Y., Fujiyama, Y., Bamba, T. (2002). IL-6 Secretion by Human Pancreatic Periacinar Myofibroblasts in Response to Inflammatory Mediators. J. Immunol. 168: 861-868 [Abstract] [Full Text]  
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• Ling, L., Goeddel, D. V. (2000). T6BP, a TRAF6-interacting protein involved in IL-1 signaling. Proc. Natl. Acad. Sci. USA 97: 9567-9572 [Abstract] [Full Text]  

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