Th17 Activation Pathway

Th17 cells are characterized by the production of IL-17A, IL-17F, IL-22 and IL-21 cytokines which promote the clearance of extracellular bacteria and fungi in the gastrointestinal tract, airway, lungs, and skin. IL-17A and IL-17F are key cytokines for the recruitment, activation, and migration of neutrophils and can induce pro-inflammatory mediators such as IL-6, TNF-β, IL-1, GM-CSF and chemokines in fibroblasts, endothelial cells, airway smooth muscle cells, and epithelial cells. IL-17 also regulates germinal-center formation and autoantibody production. IL-22 has indispensable role in immune barrier function of epithelial cells because induces antimicrobial agents and β-defensins in keratinocytes and promotes epidermal hyperplasia. IL-21 is essential in Th17 differentiation, stimulates proliferation of CD8+ T and B cells and also is a key cytokine in the cytotoxic program of NK and NKT cells.Th17 cells can be associated with the pathogenesis of several autoimmune and inflammatory diseases, such as rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis, psoriasis, inflammatory bowel disease, and allergy and asthma. Pathologies probably occur after dysregulation of the appropriate signaling that control Th17 cell proliferation or cytokine production.The complete Th17 cell differentiation consists of three different stages. The first stage is differentiation of Th17 cells triggered by the combined effect of TGF-β and IL-6/IL-21. TGF-β is essential for the induction of RORγt in naive T cells, although the expression and functions of RORγt are inhibited at high concentrations of TGF- β. The second stage is amplification of Th17 cells operated by IL-21 produced by Th17 cell themselves. The third stage is stabilization of Th17 cells by IL-23.RORγt was identified as the master transcription factor defining Th17 cells as a distinct lineage. While STAT3 seems to be a critical transcription factor for Th17 differentiation through binding and regulating Il17a and Il17f locus and the Il21 locus, as well as regulating RORγt and IL-23R expression.In addition, IL-1, AHR and PGE2 enhance Th17 development, whereas IL-2 signaling via STAT5 has a direct negative effect on IL-17A gene expression while IL-4, IL-27 and IFN-γ attenuates Th17 polarization through STAT1 and STAT6 signaling.