Interleukin 17 Family Cytokines: Signaling Mechanisms, Biological Activities, and Therapeutic Implications

Abstract

The cytokines of the interleukin 17 (IL-17) family play a central role in the control of infections, especially extracellular fungi. Conversely, if unrestrained, these inflammatory cytokines contribute to the pathology of numerous autoimmune and chronic inflammatory conditions. Recent advances have led to the approval of IL-17A-blocking biologics for the treatment of moderate to severe plaque psoriasis, but much remains to be understood about the biological functions, regulation, and signaling pathways downstream of these factors. In this review, we outline the current knowledge of signal transduction and known physiological activities of IL-17 family cytokines. We will highlight in particular the current understanding of these cytokines in the context of skin manifestations of disease.

Figure 1.

Interleukin 17 (IL-17) family cytokines and their receptors. Most IL-17 family cytokines signal via a heterodimeric receptor composed of IL-17RA and a second chain that varies depending on ligand, as indicated. Despite advances in the characterization of receptor–ligand interactions, several questions remain. Namely, a role for IL-17RA in IL-17B signaling has not been fully shown. In addition, the receptor for IL-17D, as well as the ligand for IL-17RD, remain unknown.

Figure 2.

Interleukin (IL)-17RA/RC signaling pathways. IL-17A/IL-17F/IL-17A/F binding to the receptor complex enables homotypic interactions between the SEF/IL-17R (SEFIR) domains in the receptor and in the adapter Act1/CIKS. The canonical IL-17 signaling pathway initiates signaling through Act1-induced K63-linked ubiquitylation of TRAF6, thereby activating the mitogen-activated protein kinase (MAPK), CCAAT-enhancer-binding protein β (C/EBPβ), and nuclear factor κB (NF-κB) pathways. This triggers transcriptional activation of downstream target genes, including proinflammatory cytokines, chemokines, and antimicrobial peptides. In turn, noncanonical signaling relies on Act1 phosphorylation at amino acid 311. This recruits TRAF2 and TRAF5, which sequesters the messenger RNA (mRNA)-destabilizing factor ASF/SF2 and recruits the mRNA-stabilizing factor HuR. Together, these two pathways mediate the proinflammatory functions of IL-17A, IL-17F, and IL-17A/F.

Figure 3.

Interleukin (IL)-17RA/RB signaling. On IL-17E binding to its receptor, homotypic interactions between the SEF/IL-17R (SEFIR) domains in the receptor and in the adapter Act1/CIKS are established. This leads to the recruitment of TRAF6, activating the mitogen-activated protein kinase (MAPK) and nuclear factor κB (NF-κB) signaling pathways. In turn, Act1 can recruit TRAF4, which activates the E3 ligase SMURF2. This leads to the ubiquitylation and subsequent degradation of the inhibitor DAZAP2, amplifying IL-17E-mediated signaling. In addition, IL-17RB can elicit STAT5 activation in an Act1-independent manner.