Published online before print December 30, 2009

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© by The Society for Leukocyte Biology
Journal of Leukocyte Biology, doi:10.1189/jlb.0909639

Received for publication September 26, 2009.
Revised November 11, 2009.
Accepted for publication December 1, 2009.

Article

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

Yukiko Hiramatsu ^*, Akira Suto ^*, Daisuke Kashiwakuma ^*, Hiroko Kanari ^*, Shin-ichiro Kagami ^*, Kei Ikeda , Koichi Hirose , Norihiko Watanabe , Michael J. Grusby , Itsuo Iwamoto , and Hiroshi Nakajima ^*@

*Department of Molecular Genetics, Graduate School of Medicine, Chiba University, andDepartment of Allergy and Clinical Immunology, Chiba University Hospital, Chiba, Japan;Department of Immunology and Infectious Diseases, Harvard School of Public Health, Boston, Massachusetts, USA; andResearch Center for Allergy and Clinical Immunology, Asahi General Hospital, Asahi, Chiba, Japan

^@ To whom correspondence should be addressed. E-mail: nakajimh{at}faculty.chiba-u.jp.

Abstract

Previous studies have shown that IL-6 potently induces IL-21 production in CD4⁺ T cells, whereas TGF- 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- up-regulated IL-6-induced c-Maf expression in CD4⁺ T cells, TGF- 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- suppresses c-Maf-induced IL-21 production in CD4⁺ T cells.

Key Words: Th17 cells • Foxp3 • Tfh cells • Tregs