IL-6 plays a unique role in initiating c-Maf expression during early stage of CD4 T cell activation.
The transcription factor c-Maf plays a critical and selective role in IL-4 gene transcription. Little is known about the mechanism that guides c-Maf regulation during early T cell activation. We report that IL-6 but not IL-4 or other cytokines, rapidly up-regulates c-Maf transcription, as early as 3 h after TCR activation in naive CD4(+) T cells. c-Maf induction requires both IL-6- and TCR-initiated signals, and is independent of IL-4/Stat6 signals. Cyclosporin A and FK506, which target calcineurin and thereby inhibit TCR-mediated Ca(2+) signal pathways, block IL-6-mediated c-Maf expression. We show that Stat3 binds the c-maf promoter in CD4 T cells after IL-6 stimulation, and also transactivates the c-maf promoter in reporter gene assays. IL-6 induces similar c-Maf expression in protein kinase Ctheta-deficient CD4(+) T cells. Furthermore, IL-6 enhances IL-4 gene expression very early after TCR activation in both wild-type and Stat6-deficient CD4(+) T cells. Our findings suggest that IL-6 plays a unique role in initiating c-Maf expression after TCR engagement, and may subsequently regulate early IL-4 production and Th2 commitment.
Yang
Yu
Y
Department of Gene and Cell Medicine, The Recanati/Miller Transplantation Institute, Mount Sinai School of Medicine, New York, NY 10029, USA.
Ochando
Jordi
J
Yopp
Adam
A
Bromberg
Jonathan S
JS
Ding
Yaozhong
Y
D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism*; D020013:Calcium Signaling / Q000235:genetics / Q000276:immunology; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D003713:Dendritic Cells / Q000276:immunology; D018984:Epitopes, T-Lymphocyte / Q000276:immunology; D005786:Gene Expression Regulation / Q000276:immunology; D015847:Interleukin-4 / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D015850:Interleukin-6 / Q000502:physiology*; D008213:Lymphocyte Activation / Q000235:genetics / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D011401:Promoter Regions, Genetic; D011485:Protein Binding / Q000235:genetics / Q000276:immunology; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D051257:Proto-Oncogene Proteins c-maf; D011948:Receptors, Antigen, T-Cell / Q000276:immunology / Q000378:metabolism / Q000502:physiology; D050796:STAT3 Transcription Factor; D050800:STAT6 Transcription Factor; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology*; D015534:Trans-Activators / Q000378:metabolism / Q000502:physiology; D015854:Up-Regulation / Q000235:genetics / Q000276:immunology
D004268:DNA-Binding Proteins; D018984:Epitopes, T-Lymphocyte; D015850:Interleukin-6; C495608:Maf protein, mouse; D011518:Proto-Oncogene Proteins; D051257:Proto-Oncogene Proteins c-maf; D011948:Receptors, Antigen, T-Cell; D050796:STAT3 Transcription Factor; D050800:STAT6 Transcription Factor; C494087:Stat3 protein, mouse; C494100:Stat6 protein, mouse; D015534:Trans-Activators; D015847:Interleukin-4