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. 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 selleck compound whether IL-22 and Th22 cells contribute to T cell-mediated synovial inflammation. In addition to RORγt and RORα, other transcription factors are also identified which effect differentiation and development of Th17 cells, including RORγ, STAT3, aryl hydrocarbon receptor (AhR) or dioxin receptor,[31, 32] interferon DZNeP order regulatory factor-4 (IRF-4) and a recently identified transcription factor, BATf, a basic leucine zipper transcription factor. 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. 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, ioxilan because IL-17 production in STAT1-deficient T cells is increased. 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. 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. GATA-3, c-Maf, and STAT6 are the Th2 lineage-specific transcription factors which promote Th2 differentiation and inhibit Th17 development.