[22] Possibly, impaired differentiation of Th17 cells in the absence of heterodimeric IL-23R complex is due to impaired expression of IL-17Rα.[23, 24] Also it is shown that although IL-23 is not involved in the initiation of the Th17 development program, it is required for the full terminal differentiation of Th17 and ultimately its activity.[25, 26] Recently, it was reported that IL-23 promotes Th17 differentiation

by inhibiting T-bet and FoxP3 and is required for elevation of IL-22 but not IL-21.[27] IL-22 is produced by Th17 and it was recently discovered that Th22 cells are able to produce this cytokine in the absence of IL-17. However, it remains unclear Dabrafenib datasheet whether IL-22 and Th22 cells contribute to T cell-mediated synovial inflammation.[28] In addition to RORγt and RORα, other transcription factors are also identified which effect differentiation and development of Th17 cells, including RORγ,[29] STAT3,[30] aryl hydrocarbon receptor (AhR) or dioxin receptor,[31, 32] interferon VX-770 purchase regulatory factor-4 (IRF-4)[33] and a recently identified transcription factor, BATf, a basic leucine zipper transcription factor.[26] It is revealed that

Th1 hallmark cytokines, including IFNγ and IL-12, can promote Th1 differentiation and inhibit Th17 development, since IFNγ can prevent IL-23-triggered expansion of Th17 cells.[16] Moreover, IFNγ increases T-bet expression and T-bet overexpression leads to robust reduction of IL-17 generation. Surprisingly, T-bet can promote Th17 development, because T-bet can bind to the IL-23R promoter and promote its expression.[34-37] STAT1 and STAT4 mediate IFNγ and IL-12 signaling, and it seems that these two transcription factors are also negative regulators of Th17 development, Nintedanib (BIBF 1120) because IL-17 production in STAT1-deficient T cells is increased.[16] Conversely, Th17 cell development in STAT1-, STAT4- and T-bet-deficient mice is unaffected, suggesting that these transcription factors have no significant effects in Th17 development.[38, 39] IL-27, a member of the IL-12 family

of cytokines is also the negative regulator of Th17 cells. Like the IFNγ, IL-27 signaling is through engagement of STAT1 transcription factor. The producer cells of this cytokine are macrophages and dendritic cells and their signaling are mediated through a receptor composed of IL-27R (WSX1 or TCCR) and the gp130 chain.[40-43] In addition, IFNβ inhibits Th17 development through induction of IL-27.[44] Like Th1 cells, Th2 cytokines and their transcription factors which promote Th2 development, inhibit Th17 differentiation and expansion, so that IL-4 can inhibit both Th1 and Th17 differentiation and expansion.[16] GATA-3, c-Maf, and STAT6 are the Th2 lineage-specific transcription factors which promote Th2 differentiation and inhibit Th17 development.