IL-17 Signaling

Cytokines are key messenger molecules in cell-to-cell communication and are involved in various aspects of the immune system such as maintaining homeostasis and mediating and resolving pathologic conditions. IL-17 (Interleukin-17) family is a group of cytokines sharing homology in amino acid sequences with highly conserved cysteine residues critical to their 3-dimensional shape. IL-17, the signature cytokine secreted by Th17 cells, is required for host defence against extracellular bacterial and fungal infections, and contributes to the pathogenesis of various autoimmune inflammatory diseases. IL-17 has become an important target for treating different forms of inflammatory disorders. Recent clinical trials with agents that target IL-17/IL-17R, the upstream regulation pathways of IL-17 expression and the downstream signaling pathways of IL-17 hold promise for treating autoimmune diseases. So far, six members, IL-17A (commonly refer to IL-17), IL-17B, IL-17C, IL-17D, IL-17E (also called IL-25) and IL-17F, have been identified. The IL-17R family contains five receptor subunits, IL-17RA–IL-17RE. Both IL-17 members and IL-17Rs have little homology to other known cytokines or cytokine receptors, and are classified as new cytokine and cytokine receptor families.IL-17 signals through a heteromeric receptor complex formed by IL-17R (IL-17RA) and IL-17RC, which are single-pass transmembrane proteins expressed by a variety of cells including astrocytes and microglia. IL-17RA can be bound by both IL-17A and IL-17F, but with 10-fold more affinity for IL-17A than for IL-17F. While both IL-17E and IL-17B bind IL-17RB, to induce Th2 cytokines, the ligand for IL-17RD is still unknown. IL-17C may be the ligand for IL-17RE, but the functional link needs to be identified. Binding of the first IL-17 receptor subunit to the ligand modulates the affinity and specificity of the second-binding event, thereby promoting heterodimeric versus homodimeric complex formation. Three remaining cytokines in the IL-17 family, IL-17B, IL-17C and IL-17D, currently are poorly studied with regards to their biological function and receptors.IL-17C which binds to the IL-17RE–IL-17RA heterodimeric complex is also important for host defence and autoimmunity (Ref.1, 2, 3&4).

IL-17A is a founding member of the IL-17 family and serves as an essential player in host defense during infection while aberrant expression of IL-17A is associated with many autoimmune diseases and cancer. IL-17A is a pleiotropic cytokine that acts on multiple cell types to enhance the production of proinflammatory molecules. IL-17 binds to the IL-17RA or IL-17RC as homodimers or heterodimers. Once IL-17F is secreted from CD4 and CD T-cells, it is recognized by IL-17RA/RC heteromeric complex. IL-17RA, then, recruits the adaptor molecule, Act1. Act1 activates TRAF6 as well as other transcription factors, leading to induction of cytokines, chemokines and MMPs (matrix metalloproteinase) genes. In addition, the presence of IL-17A/F heterodimers substantially influences the potency, specificity and the spectrum of the activity of these cytokines. Therefore, future studies should be directed to understand the mechanism and role of IL-17F and its related cytokines and provide a platform for development of therapeutic intervention for inflammatory diseases (Ref.5, 6, 7&8) .IL-17 has been shown to activate many common downstream signalling pathways, including NF-KappaB (Nuclear Factor-KappaB), the MAPKs: JNK (c-Jun N-terminal Kinase), p38 and ERK (Extracellular-signal regulated kinase), C/EBPbeta/gamma, PI3K and JAK/STATs. Signaling by PI3K through Akt leads to up-regulation of IL-17RA. Akt in turn phosphorylates a number of downstream targets that cumulatively serve to promote cell survival, including GSK3-Alpha/Beta (Ref.9&10). Another important function of IL-17 is that it can stabilize the mRNA of some proinflammatory cytokines and chemokines induced by TNF (Tumor Necrosis Factor). TRAF3 (TNF Receptor-Associated Factor-3) is a proximal negative regulator of the IL-17R and suppresses IL-17-mediated downstream events through interfering with the formation of the receptor signaling activation complex IL-17R–Act1–TRAF6 (Ref.2, 3, 11&12).

A unique TRAF6-independent signaling pathway activated by IL-1 .IKKi is recruited to the IL-17R–Act1 complex, where it specifically phosphorylates Act1 at Ser311. This generates a docking site that recruits TRAF2 and TRAF5 but not TRAF6. In the absence of IL-17, SF2 (ASF) binds to the 3′ UTR of CXCL1 mRNA, causing its instability. After stimulation with IL-17, SF2 (ASF) associates with the TRAF2–TRAF5–Act1 complex, relieving the repression of CXCL1 mRNA and prolonging its half-life. Although this synergy requires the recruitment of Act1 to IL-17R, it occurs via TRAF6-independent stabilization of mRNA, which indicates the existence of an Act1-dependent, TRAF6-independent sig¬naling cascade separate from IL-17-induced activation of NF-κB. In addition, IL-17 activates mitogen-activated protein kinases in an Act1-dependent, TRAF6-independent manner, which further suggests that Act1 is an important bifurcation point for TRAF6-dependent and TRAF6-independent IL-17R signaling events (Ref.13).

IL-25, also known as IL-17E, is a high affinity ligand for IL-17RB. IL-17B is also reported to bind to IL-17RB with an affinity of 7.6 nM, while IL-25 binds to IL-17RB with Kd value of 1.1–1.4 nM. IL-25 appears to promote the expansion and further polarization of Th2 central memory cells .IL-17RA and IL-17RB as a signaling complex for IL-25 signaling.IL-17RA bound to the IL-17RB-IL-25 complex with an affinity of 14.1 ± 2.4 μM (Ref.14).Act1, the adaptor of IL-17RA signaling, is also involved in IL-17RB signaling. The interaction between Act1 and IL-17RB was abolished when the SEFIR domain was deleted in either Act1 or IL-17RB, indicating the recruitment of Act1 to IL-17RB is through the dimerization of the SEFIR domain.TRAF6 was implicated in IL-17RA signaling, NF-KappaB activation mediated through IL-17RB is abrogated in TRAF6 deficient cells, indicating IL-25 may acquire similar signaling pathways as IL-17. However, IL-25 activates ERK, JNK, and p38 by a TRAF6-independent mechanism. In contrary to IL-17RA that lacks TRAF6 binding sites, IL-17RB possesses TRAF6 binding sites. IL-17RB -mediated NF-B activation was attenuated in cells expressing in IL-17RB E338A, in which TRAF6-binding motif was mutated. IL-25 induces expression of GATA-3, c-maf, and JunB by activated Th2 memory cells. It is not known whether IL-25 mediates the signaling in CD4 T cells through TRAF6 and Act1 or there is independent pathway. In epithelial cells, IL-17RB is known to activate NF-KappaB and MAPK pathways through TRAF6 and TAK1. IL-17 has been associated with the pathogenesis of multiple autoimmune diseases including rheumatoid arthritis, multiple sclerosis and inflammatory bowel diseases. IL-17 is also important for host defence, further investigations into IL-17-mediated signaling to dissect the inflammatory pathway compared with the host defence pathway, and subsequent immunological and pathogenic roles of potential signaling targets, will help in the development of more specific medicines for alleviating symptoms associated with autoimmune inflammatory diseases without compromising host defence (Ref.1, 2&3).