IL-17 family: cytokines, receptors and signaling

Abstract

The interleukin 17 (IL-17) family, a subset of cytokines consisting of IL-17A-F, plays crucial roles in host defense against microbial organisms and in the development of inflammatory diseases. Although IL-17A is the signature cytokine produced by T helper 17 (Th17) cells, IL-17A and other IL-17 family cytokines have multiple sources ranging from immune cells to non-immune cells. The IL-17 family signals via their correspondent receptors and activates downstream pathways that include NFκB, MAPKs and C/EBPs to induce the expression of anti-microbial peptides, cytokines and chemokines. The proximal adaptor Act1 is a common mediator during the signaling of all IL-17 cytokines so far and is thus involved in IL-17 mediated host defense and IL-17-driven autoimmune conditions. This review will give an overview and recent updates on the IL-17 family, the activation and regulation of IL-17 signaling as well as diseases associated with this cytokine family.

Keywords: Act1; IL-17R; Interleukin 17; Signaling transduction.

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.

Figure 2

The structure of Act1. Act1 contains two TRAF binding motifs (TB1 and TB2) that mediate TRAF6 and TRAF4 interactions following IL-17 stimulation. The U-box E3 ligase domain is functionally important for mediating the ubiquitination of its target proteins, like TRAF6 and HuR. The SEFIR domain of Act1 is necessary for the recruitment of Act1 to the IL-17 receptor upon IL-17 stimulation. At the N-terminus, a highly conserved region is required for Act1’s interaction with the molecular chaperone, Hsp90.