IL-17-induced NF-κB Activation via CIKS/Act1 PHYSIOLOGIC SIGNIFICANCE AND SIGNALING MECHANISMS

Interleukin-17 (IL-17) is essential in host defense against extracellular bacteria and fungi, especially at mucosal sites, but it also contributes significantly to inflammatory and autoimmune disease pathologies. Binding of IL-17 to its receptor leads to recruitment of adaptor protein CIKS/Act1 via heterotypic association of their respective SEFIR domains and activation of transcription factor NF-kappa B; it is not known whether CIKS and/or NE-kappa B are required for all gene induction events. Here we report that CIKS is essential for all IL-17-induced immediate-early genes in primary mouse embryo fibroblasts, whereas NF-kappa B is profoundly involved. We also identify a novel subdomain in the N terminus of CIKS that is essential for IL-17-mediated NF-kappa B activation. This domain is both necessary and sufficient for interaction between CIKS and TRAF6, an adaptor required for NF-kappa B activation. The ability of decoy peptides to block this interaction may provide a new therapeutic strategy for intervention in IL-17-driven autoimmune and inflammatory diseases.