title: c-Maf activates the promoter and enhancer of the IL-21 gene, and TGF-beta inhibits c-Maf-induced IL-21 production in CD4+ T cells.
abstract: 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.
authors.affiliation: Department of Molecular Genetics, Graduate School of Medicine, Chiba University, Chiba 260-8670, Japan.
authors.forename: Yukiko
authors.initials: Y
authors.lastname: Hiramatsu
authors.forename: Akira
authors.initials: A
authors.lastname: Suto
authors.forename: Daisuke
authors.initials: D
authors.lastname: Kashiwakuma
authors.forename: Hiroko
authors.initials: H
authors.lastname: Kanari
authors.forename: Shin-ichiro
authors.initials: S
authors.lastname: Kagami
authors.forename: Kei
authors.initials: K
authors.lastname: Ikeda
authors.forename: Koichi
authors.initials: K
authors.lastname: Hirose
authors.forename: Norihiko
authors.initials: N
authors.lastname: Watanabe
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Grusby
authors.forename: Itsuo
authors.initials: I
authors.lastname: Iwamoto
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Nakajima
mesh_terms: D000818:Animals; D019898:Autocrine Communication / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism*; D004742:Enhancer Elements, Genetic / Q000502:physiology*; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D015847:Interleukin-4 / Q000276:immunology / Q000378:metabolism; D015850:Interleukin-6 / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology; D007378:Interleukins / Q000096:biosynthesis* / Q000235:genetics / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D011401:Promoter Regions, Genetic / Q000502:physiology*; D051257:Proto-Oncogene Proteins c-maf / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D050800:STAT6 Transcription Factor; D016212:Transforming Growth Factor beta / Q000276:immunology / Q000378:metabolism*; D015854:Up-Regulation / Q000276:immunology; D000098546:Interleukin-21
chemical_list: D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D015850:Interleukin-6; D007378:Interleukins; C495608:Maf protein, mouse; D051257:Proto-Oncogene Proteins c-maf; D050800:STAT6 Transcription Factor; C494100:Stat6 protein, mouse; D016212:Transforming Growth Factor beta; D015847:Interleukin-4; D000098546:Interleukin-21