IL-17A Signaling in Fibroblasts

Th17 is a distinct subset of T cells known to produce a variety of pro-inflammatory cytokines that link adaptive and innate immunity. IL-17A is the signature cytokine produced by Th17 cells. It is also the most studied member of a family of 6 ligands which also includes IL-17B, IL-17C, IL-17D, IL-17E and IL-17F. These cytokines consist of 163-202 amino acids with molecular masses of 20-30 kDa. IL-17A (also known as IL-17) is most homologous to IL-17F (~60%). IL-17A is a disulfide-linked homodimeric glycoprotein consisting of 155 amino acids which binds to and activates a heterodimeric transmembrane receptor complex consisting of IL-17RC and IL-17RA subunits. Functionally, IL-17A has been linked to the pathogenesis of diverse autoimmune and inflammatory diseases. In contrast, it also plays a role in host defense against extracellular microorganisms.IL-17A signaling in fibroblasts is mainly mediated via NF-κB, a hallmark transcription factor associated with inflammation, and C/EBP, another well-studied transcription factor. IL-17A induces the sequential phosphorylation of Thr188 and Thr 179 within the C/EBPβ RD2 domain. The former phosphorylation is mediated by ERKs while the latter is mediated by GSK3β. Surprisingly, IL-17A induced phosphorylation of C/EBPβ results in the negative regulation of genes such as IL-6, CCL2 and LCN2. There is also an interplay between the transcription factors NF-κB and C/EBP wherein IL-17A induces the expression of C/EBPδ and C/EBPβ mRNA via the ACT1/TRAF6/TAK1/NK-κB signaling pathway.IL-17A has been shown to induce MMP-1 expression in human cardiac fibroblasts. Stimulation of MMP-1 transcription is mediated by NF-κB, AP-1, and C/EBPβ activation. Cardiac fibroblast migration was shown to be dependent on IL-17A induced MMP-1. Since MMPs degrade extracellular matrix and facilitate migration, IL-17 may be potentially important in myocardial remodeling.