Brief Definitive Report

Requirement of Tumor Necrosis Factor Receptor–associated Factor (TRAF)6 in Interleukin 17 Signal Transduction

Correspondence to: Zhaodan Cao, Tularik Inc., Two Corporate Dr., South San Francisco, CA 94080. Tel:650-825-7481 Fax:650-825-7400 E-mail: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

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

• 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]  
• Yang, X. O., Chang, S. H., Park, H., Nurieva, R., Shah, B., Acero, L., Wang, Y.-H., Schluns, K. S., Broaddus, R. R., Zhu, Z., Dong, C. (2008). Regulation of inflammatory responses by IL-17F. JEM 205: 1063-1075 [Abstract] [Full Text]  
• Huang, F., Kao, C.-Y., Wachi, S., Thai, P., Ryu, J., Wu, R. (2007). Requirement for Both JAK-Mediated PI3K Signaling and ACT1/TRAF6/TAK1-Dependent NF-{kappa}B Activation by IL-17A in Enhancing Cytokine Expression in Human Airway Epithelial Cells. J. Immunol. 179: 6504-6513 [Abstract] [Full Text]  
• Kuestner, R. E., Taft, D. W., Haran, A., Brandt, C. S., Brender, T., Lum, K., Harder, B., Okada, S., Ostrander, C. D., Kreindler, J. L., Aujla, S. J., Reardon, B., Moore, M., Shea, P., Schreckhise, R., Bukowski, T. R., Presnell, S., Guerra-Lewis, P., Parrish-Novak, J., Ellsworth, J. L., Jaspers, S., Lewis, K. E., Appleby, M., Kolls, J. K., Rixon, M., West, J. W., Gao, Z., Levin, S. D. (2007). Identification of the IL-17 Receptor Related Molecule IL-17RC as the Receptor for IL-17F. J. Immunol. 179: 5462-5473 [Abstract] [Full Text]  
• 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]  
• Yu, J. J., Ruddy, M. J., Wong, G. C., Sfintescu, C., Baker, P. J., Smith, J. B., Evans, R. T., Gaffen, S. L. (2007). An essential role for IL-17 in preventing pathogen-initiated bone destruction: recruitment of neutrophils to inflamed bone requires IL-17 receptor-dependent signals. Blood 109: 3794-3802 [Abstract] [Full Text]  
• Wozniak, T. M., Ryan, A. A., Britton, W. J. (2006). Interleukin-23 Restores Immunity to Mycobacterium tuberculosis Infection in IL-12p40-Deficient Mice and Is Not Required for the Development of IL-17-Secreting T Cell Responses. J. Immunol. 177: 8684-8692 [Abstract] [Full Text]  
• 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]  
• Tran, E. H., Azuma, Y.-T., Chen, M., Weston, C., Davis, R. J., Flavell, R. A. (2006). Inactivation of JNK1 enhances innate IL-10 production and dampens autoimmune inflammation in the brain. Proc. Natl. Acad. Sci. USA 103: 13451-13456 [Abstract] [Full Text]  
• Shen, F., Hu, Z., Goswami, J., Gaffen, S. L. (2006). Identification of Common Transcriptional Regulatory Elements in Interleukin-17 Target Genes. J. Biol. Chem. 281: 24138-24148 [Abstract] [Full Text]  
• Toy, D., Kugler, D., Wolfson, M., Bos, T. V., Gurgel, J., Derry, J., Tocker, J., Peschon, J. (2006). Cutting Edge: Interleukin 17 Signals through a Heteromeric Receptor Complex. J. Immunol. 177: 36-39 [Abstract] [Full Text]  
• Koenders, M. I., Lubberts, E., van de Loo, F. A. J., Oppers-Walgreen, B., van den Bersselaar, L., Helsen, M. M., Kolls, J. K., Di Padova, F. E., Joosten, L. A. B., van den Berg, W. B. (2006). Interleukin-17 Acts Independently of TNF-{alpha} under Arthritic Conditions. J. Immunol. 176: 6262-6269 [Abstract] [Full Text]  
• Kramer, J. M., Yi, L., Shen, F., Maitra, A., Jiao, X., Jin, T., Gaffen, S. L. (2006). Cutting Edge: Evidence for Ligand-Independent Multimerization of the IL-17 Receptor. J. Immunol. 176: 711-715 [Abstract] [Full Text]  
• Maezawa, Y., Nakajima, H., Suzuki, K., Tamachi, T., Ikeda, K., Inoue, J.-i., Saito, Y., Iwamoto, I. (2006). Involvement of TNF Receptor-Associated Factor 6 in IL-25 Receptor Signaling. J. Immunol. 176: 1013-1018 [Abstract] [Full Text]  
• Lubberts, E., Schwarzenberger, P., Huang, W., Schurr, J. R., Peschon, J. J., van den Berg, W. B., Kolls, J. K. (2005). Requirement of IL-17 Receptor Signaling in Radiation-Resistant Cells in the Joint for Full Progression of Destructive Synovitis. J. Immunol. 175: 3360-3368 [Abstract] [Full Text]  
• de Haij, S., Bakker, A. C., van der Geest, R. N., Haegeman, G., Vanden Berghe, W., Aarbiou, J., Daha, M. R., van Kooten, C. (2005). NF-{kappa}B Mediated IL-6 Production by Renal Epithelial Cells Is Regulated by C-Jun NH2-Terminal Kinase. J. Am. Soc. Nephrol. 16: 1603-1611 [Abstract] [Full Text]  
• Faour, W. H., Alaaeddine, N., Mancini, A., He, Q. W., Jovanovic, D., Di Battista, J. A. (2005). Early Growth Response Factor-1 Mediates Prostaglandin E2-dependent Transcriptional Suppression of Cytokine-induced Tumor Necrosis Factor-{alpha} Gene Expression in Human Macrophages and Rheumatoid Arthritis-affected Synovial Fibroblasts. J. Biol. Chem. 280: 9536-9546 [Abstract] [Full Text]  
• Shen, F., Ruddy, M. J., Plamondon, P., Gaffen, S. L. (2005). Cytokines link osteoblasts and inflammation: microarray analysis of interleukin-17- and TNF-{alpha}-induced genes in bone cells. J. Leukoc. Biol. 77: 388-399 [Abstract] [Full Text]  
• Yamazaki, S., Muta, T., Matsuo, S., Takeshige, K. (2005). Stimulus-specific Induction of a Novel Nuclear Factor-{kappa}B Regulator, I{kappa}B-{zeta}, via Toll/Interleukin-1 Receptor Is Mediated by mRNA Stabilization. J. Biol. Chem. 280: 1678-1687 [Abstract] [Full Text]  
• Linden, A., Laan, M., Anderson, G. P. (2005). Neutrophils, interleukin-17A and lung disease. Eur Respir J 25: 159-172 [Abstract] [Full Text]  
• Ruddy, M. J., Wong, G. C., Liu, X. K., Yamamoto, H., Kasayama, S., Kirkwood, K. L., Gaffen, S. L. (2004). Functional Cooperation between Interleukin-17 and Tumor Necrosis Factor-{alpha} Is Mediated by CCAAT/Enhancer-binding Protein Family Members. J. Biol. Chem. 279: 2559-2567 [Abstract] [Full Text]  
• Wan, J., Sun, L., Mendoza, J. W., Chui, Y. L., Huang, D. P., Chen, Z. J., Suzuki, N., Suzuki, S., Yeh, W.-C., Akira, S., Matsumoto, K., Liu, Z.-g., Wu, Z. (2004). Elucidation of the c-Jun N-Terminal Kinase Pathway Mediated by Epstein-Barr Virus-Encoded Latent Membrane Protein 1. Mol. Cell. Biol. 24: 192-199 [Abstract] [Full Text]  
• Chiffoleau, E., Kobayashi, T., Walsh, M. C., King, C. G., Walsh, P. T., Hancock, W. W., Choi, Y., Turka, L. A. (2003). TNF Receptor-Associated Factor 6 Deficiency during Hemopoiesis Induces Th2-Polarized Inflammatory Disease. J. Immunol. 171: 5751-5759 [Abstract] [Full Text]  
• Faour, W. H., Mancini, A., He, Q. W., Di Battista, J. A. (2003). T-cell-derived Interleukin-17 Regulates the Level and Stability of Cyclooxygenase-2 (COX-2) mRNA through Restricted Activation of the p38 Mitogen-activated Protein Kinase Cascade: ROLE OF DISTAL SEQUENCES IN THE 3'-UNTRANSLATED REGION OF COX-2 mRNA. J. Biol. Chem. 278: 26897-26907 [Abstract] [Full Text]  
• Hellings, P. W., Kasran, A., Liu, Z., Vandekerckhove, P., Wuyts, A., Overbergh, L., Mathieu, C., Ceuppens, J. L. (2003). Interleukin-17 Orchestrates the Granulocyte Influx into Airways after Allergen Inhalation in a Mouse Model of Allergic Asthma. Am. J. Respir. Cell Mol. Bio. 28: 42-50 [Abstract] [Full Text]  
• Hull, C., McLean, G., Wong, F., Duriez, P. J., Karsan, A. (2002). Lipopolysaccharide Signals an Endothelial Apoptosis Pathway Through TNF Receptor-Associated Factor 6-Mediated Activation of c-Jun NH2-Terminal Kinase. J. Immunol. 169: 2611-2618 [Abstract] [Full Text]  
• Benchetrit, F., Ciree, A., Vives, V., Warnier, G., Gey, A., Sautes-Fridman, C., Fossiez, F., Haicheur, N., Fridman, W. H., Tartour, E. (2002). Interleukin-17 inhibits tumor cell growth by means of a T-cell-dependent mechanism. Blood 99: 2114-2121 [Abstract] [Full Text]  
• 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]  
• Lubberts, E., Joosten, L. A. B., Oppers, B., van den Bersselaar, L., Coenen-de Roo, C. J. J., Kolls, J. K., Schwarzenberger, P., van de Loo, F. A. J., van den Berg, W. B. (2001). IL-1-Independent Role of IL-17 in Synovial Inflammation and Joint Destruction During Collagen-Induced Arthritis. J. Immunol. 167: 1004-1013 [Abstract] [Full Text]  
• Ling, L., Goeddel, D. V. (2000). T6BP, a TRAF6-interacting protein involved in IL-1 signaling. Proc. Natl. Acad. Sci. USA 10.1073/pnas.170279097v1 [Abstract] [Full Text]  
• Lee, J., Ho, W.-H., Maruoka, M., Corpuz, R. T., Baldwin, D. T., Foster, J. S., Goddard, A. D., Yansura, D. G., Vandlen, R. L., Wood, W. I., Gurney, A. L. (2001). IL-17E, a Novel Proinflammatory Ligand for the IL-17 Receptor Homolog IL-17Rh1. J. Biol. Chem. 276: 1660-1664 [Abstract] [Full Text]  
• 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]  

Home | Help | Feedback | Subscriptions | Archive | Search

TABLE OF CONTENTS