Figure 1. IL-17 cytokines, receptors and signaling.

The IL-17 family consists of six members IL-17A-F, while the IL-17 receptor family consists of five members IL-17RA to IL-17RE. IL-17RA is a common receptor that forms heterodimeric complexes with IL-17RB, IL-17RC, and IL-17RE. Thus far, all of the IL-17 receptors recruit Act1 as an adaptor molecule for downstream signaling. IL-17A and IL-17F signals through the IL-17RA-RC complex, triggering TRAF6-dependent target gene transcription and TRAF6-independent IKKi-dependent mRNA stabilization, both of which are important for host defense and contributes to the pathogenesis of autoimmune diseases and cancer. IL-17 signaling is tightly controlled at different levels of the signaling cascade. At the receptor level, IL-17RD interacts with Act1 basally, sequestering it from IL-17RA and TRAF6 until IL-17 stimulation. TRAFs like TRAF3 and TRAF4 act to disrupt downstream signaling complex formation. While TRAF3 binds to the IL-17R to prevent the recruitment of Act1 and TRAF6, TRAF4 competes with TRAF6 for Act1 binding. Deubiquitinating enzymes like USP25 and A20 regulate the ubiquitination status of TRAFs (like TRAF5 and TRAF6), placing a brake on the signaling cascade. The IL-17A-dependent micro-RNA, miR-23b, regulates NFκB activation. IL-17A-induced transcription factors such as C/EBPδ inhibits inflammatory gene expression. IL-17E (IL-25) signaling through the IL-17RA-RBreceptor complex induces Th2 responses by activating MAPK and NFκB pathways. IL-17C signals through the IL-17RA-RE complex mediates host defense and like IL-17A, contributes to the pathogenesis of autoimmune diseases. IL-17B have been shown to interact with IL-17RB, however, its biological function is as yet unclear. The receptor for IL-17D is unknown.