c‐Maf activates the promoter and enhancer of the IL‐21 gene, and TGF‐β inhibits c‐Maf‐induced IL‐21 production in CD4+ T cells

Previous studies have shown that IL‐6 potently induces IL‐21 production in CD4+ T cells, whereas TGF‐β inhibits IL‐6‐induced IL‐21 production in CD4+ T cells. In this study, we addressed the mechanisms underlying the transcriptional regulation of IL‐21 production in CD4+ T cells. We found that IL‐6 induced c‐Maf expression in CD4+ T cells and that the enforced expression of c‐Maf induced IL‐21 production in CD4+ T cells without IL‐6, IL‐4/STAT6 signaling, or an autocrine effect of IL‐21. Moreover, we found that c‐Maf directly bound to and activated IL‐21P and the CNS‐2 enhancer through MARE sites. On the other hand, we also found that although TGF‐β up‐regulated IL‐6‐induced c‐Maf expression in CD4+ T cells, TGF‐β inhibited c‐Maf‐induced IL‐21 production in CD4+ T cells. Finally, we found that Foxp3 bound to IL‐21P and the CNS‐2 enhancer and inhibited c‐Maf‐induced IL‐21 production modestly but significantly in CD4+ T cells. Taken together, these results suggest that c‐Maf induces IL‐21 production directly in CD4+ T cells by activating IL‐21P and the CNS‐2 enhancer and that TGF‐β suppresses c‐Maf‐induced IL‐21 production in CD4+ T cells.

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