c-Maf directly induces IL-21 expression by activating IL-21 promoter and CNS-2 enhancer through MARE site and TGF-β suppresses c-Maf-induced IL-21 expression.

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.