Department of Molecular Genetics, Graduate School of Medicine, Chiba University, Chiba 260-8670, Japan.
J Leukoc Biol. 2010 Apr;87(4):703-12. doi: 10.1189/jlb.0909639. Epub 2009 Dec 30.
Previous studies have shown that IL-6 potently induces IL-21 production in CD4(+) T cells, whereas TGF-beta 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-beta up-regulated IL-6-induced c-Maf expression in CD4(+) T cells, TGF-beta 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-beta suppresses c-Maf-induced IL-21 production in CD4(+) T cells.
先前的研究表明，IL-6 能强烈诱导 CD4+T 细胞中产生 IL-21，而 TGF-β则抑制 CD4+T 细胞中 IL-6 诱导的 IL-21 产生。在这项研究中，我们研究了 CD4+T 细胞中 IL-21 产生的转录调控的机制。我们发现，IL-6 在 CD4+T 细胞中诱导 c-Maf 的表达，而强制表达 c-Maf 可在没有 IL-6、IL-4/STAT6 信号或 IL-21 的自分泌作用的情况下诱导 CD4+T 细胞产生 IL-21。此外，我们发现 c-Maf 通过 MARE 位点直接结合并激活 IL-21P 和 CNS-2 增强子。另一方面，我们还发现，尽管 TGF-β上调了 CD4+T 细胞中 IL-6 诱导的 c-Maf 表达，但 TGF-β 抑制了 CD4+T 细胞中 c-Maf 诱导的 IL-21 产生。最后，我们发现 Foxp3 结合到 IL-21P 和 CNS-2 增强子上，并适度但显著地抑制了 CD4+T 细胞中 c-Maf 诱导的 IL-21 产生。综上所述，这些结果表明 c-Maf 通过激活 IL-21P 和 CNS-2 增强子直接诱导 CD4+T 细胞产生 IL-21，而 TGF-β 抑制 CD4+T 细胞中 c-Maf 诱导的 IL-21 产生。
