IL-17 Signaling: The Yin and the Yang

Abstract

Interleukin (IL)-17 is the founding member of a novel family of inflammatory cytokines. While the proinflammatory properties of IL-17 are key to its host-protective capacity, unrestrained IL-17 signaling is associated with immunopathology, autoimmune disease, and cancer progression. In this review we discuss both the activators and the inhibitors of IL-17 signal transduction, and also the physiological implications of these events. We highlight the surprisingly diverse means by which these regulators control expression of IL-17-dependent inflammatory genes, as well as the major target cells that respond to IL-17 signaling.

Figure 1. IL-17 Cytokine and Receptor Family

IL-17A is the prototypical cytokine of IL-17 family that includes five other cytokines. IL-17 receptor family consists of five different receptors, which share a common cytoplasmic motif known as SEFIR domain. IL-17RA, the common subunit for all the other receptors, also consists of an inhibitory CBAD domain [SEFIR:similar expression of fibroblast growth factor and IL-17Rs, SEFEX:SEFIR extension, CBAD:C/EBPβ activation domain]

Figure 2. Major Inflammatory Genes Regulated by IL-17

IL-17 signaling controls inflammation by regulating expression of inflammatory genes in the cells of mostly non-hematopoietic compartment. The IL-17 signature genes (top left) are common inflammatory genes regulated by IL-17. Genes listed elsewhere are specific to respective tissue compartments and play a critical role in mediating tissue specific IL-17-dependent inflammation.

Figure 3. Activation of IL-17 Signal Transduction

IL-17 signaling starts with the binding of IL-17A/A, IL-17A/F or IL-17F/F cytokine to their receptors IL-17RA and IL-17RC. Upon ligand binding, Act1 activates multiple independent signaling pathways mediating through different TRAF proteins. Activation of TRAF6 results in the triggering of NF-κB, C/EBPβ, C/EBPδ and MAPK pathways. IL-17R-Act1 complex also associates with MEKK3 and MEK5 via TRAF4, resulting in the activation of ERK5. WhileTRAF6 and TRAF4-mediated IL-17 signaling results in transcription of inflammatory genes, IL-17 signaling through ACT1-TRAF2-TRAF5 complex results in the control of mRNA stability of IL-17 target genes. [Hsp: heat-shock protein, TRAF: TNF receptor associated factor, TAK1: TGF-β activated kinase 1, IKK: inhibitor of kappa B kinase, ERK: extracellular signal related kinase, JNK: Janus kinase, HuR: human antigen R, also known as ELVAL1, SF2: splicing factor 2]

Figure 4. Negative regulation of IL-17 signal transduction

Different classes of inhibitors such as ubiquitinases (TRAF3, TRAF4 and βTrCP), deubiquitinases (A20 and USP25), kinases (TBK1, GSK3β), endoribonuclease (MCPIP1/Regnase-1) and micro RNAs(miR-23b and miR-30a) negatively regulate IL-17 signaling through various independent mechanisms (see Table 1). [TRAF: TNF receptor associated factor, HuR: human antigen R, also known as ELVAL1, SF2: splicing factor 2, TAK1: TGF-β activated kinase 1, IKK: inhibitor of kappa B kinase, TBK1: TANK-binding kinase 1, GSK: glycogen synthase kinase, MAPK: mitogen-activated protein kinase]