Role of IL-17A in Arthritis

IL-17A (also referred to as IL-17) is a cytokine of the TH17 cell lineage. It is a member of the family of IL-17 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. They share four conserved cysteine residues at the C-terminal region that may participate in the formation of intermolecular disulfide linkages. IL-17A is mainly produced by Th17 cells. It 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.IL-17A has been implicated in the pathogenesis of autoimmune diseases such as rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), psoriasis and experimental autoimmune encephalomyelitis(EAE). Elevated levels of this cytokine have been recorded in the synovial fluid of patients with RA and osteoarthritis. Studies show that IL-17A induces pro-inflammatory cytokines that contribute to RA flare-ups and establish a chronic inflammatory state. IL-17A also induces chemokines such as CCL2, IL-8 and CXCL-1 which recruit neutrophils, monocytes and lymphocytes to the synovium thereby enhancing inflammation. Furthermore, IL-17A induced MMP production drives the degradation of extracellular matrix leading to cartilage damage.In chondrocytes of osteoarthritic patients, IL-17A is able to induce the expression of COX-2 and iNOS which increase levels of PGE2 and NO, respectively. The IL-17A induced increase in COX-2 expression is mediated by p38 MAPK activation of ATF-2, while iNOS is induced by activated NF-κB. COX-2 enhances inflammation by various mechanisms including vasodilation. NO contributes to structural joint alteration mainly by inducing production of peroxynitrite which in then triggers cartilage catabolism while inhibiting chondrocyte anabolism. Thus, IL-17A contributes to the pathogenesis of arthritis.