Signaling of interleukin-17 family cytokines in immunity and inflammation

Abstract

IL-17 cytokine family, though still young since discovery, has recently emerged as critical players in immunity and inflammatory diseases. The prototype cytokine, IL-17A, plays essential roles in promoting inflammation and host defense. IL-17RA, a member of the IL-17 receptor family, forms a complex with another member, IL-17RC, to mediate effective signaling for IL-17A as well as IL-17F, which is most similar to IL-17A, via Act1 and TRAF6 factors. On the other hand, IL-17RA appears to interact with IL-17RB to regulate signaling by another cytokine IL-25. IL-25, the most distant from IL-17A in the IL-17 family, is involved in allergic disease and defense against helminthic parasites. In this review, we discuss recent advancements on signaling mechanisms and biological functions of IL-17A, IL-17F and IL-25, which will shed light on the remaining IL-17 family cytokines and help understand and treat inflammatory diseases.

Figure 1. IL-17 cytokine family, their receptors and membrane proximal adaptors

IL-17, IL-17F and IL-17A/F are produced by CD4 Th17 cells, γδ T cells and ILCs (Innate lymphoid cells such as iNKT, NKp46+ and LTi-like cell). IL-25 has been detected in epithelial cells and granulocytes such as eosinophils, mast cells, basophils. IL-17RA/ IL-17RC is a signaling complex for IL-17, IL-17F and IL-17A/F. IL-17RA and IL-17RB mediate IL-25 signaling. IL-17R family shares a SEFIR motif that recruits Act1 and TRAF6 for signaling complex.