title: Glycogen synthase kinase-3 controls IL-10 expression in CD4(+) effector T-cell subsets through epigenetic modification of the IL-10 promoter.
abstract: The serine/threonine kinase glycogen synthase kinase-3 (GSK3) plays an important role in balancing pro- and anti-inflammatory cytokines. We have examined the role of GSK3 in production of IL-10 by subsets of CD4(+) T helper cells. Treatment of naive murine CD4(+) T cells with GSK3 inhibitors did not affect their production of IL-10. However, treatment of Th1 and Th2 cells with GSK3 inhibitors dramatically increased production of IL-10. GSK3 inhibition also led to upregulation of IL-10 among Th1, Th2, and Th17 subsets isolated from human blood. The encephalitogenic potential of GSK3 inhibitor treated murine Th1 cells was significantly reduced in adoptive transfer experiments by an IL-10-dependent mechanism. Analysis of the murine IL-10 promoter in response to inhibition of GSK3 in Th1 cells showed modification to a transcriptionally active state indicated by changes in histone H3 acetylation and methylation. Additionally, GSK3 inhibition increased expression of the transcription factors c-Maf, Nfil3, and GATA3, correlating with the increase in IL-10. These findings are important in the context of autoimmune disease since they show that it is possible to reprogram disease-causing cells through GSK3 inhibition.
authors: School of Cellular and Molecular Medicine, University of Bristol, Bristol, UK.
authors: Elaine V
authors: EV
authors: Hill
authors: T H Sky
authors: TH
authors: Ng
authors: Bronwen R
authors: BR
authors: Burton
authors: Charly M
authors: CM
authors: Oakley
authors: Karim
authors: K
authors: Malik
authors: David C
authors: DC
authors: Wraith
mesh_terms: D000107:Acetylation; D019264:Adoptive Transfer; D000818:Animals; D050976:Basic-Leucine Zipper Transcription Factors / Q000096:biosynthesis; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000276:immunology; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology; D050990:GATA3 Transcription Factor / Q000096:biosynthesis; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D006657:Histones / Q000378:metabolism; D006801:Humans; D007249:Inflammation / Q000276:immunology; D016753:Interleukin-10 / Q000096:biosynthesis* / Q000235:genetics; D008745:Methylation; D051379:Mice; D018345:Mice, Knockout; D011401:Promoter Regions, Genetic; D051257:Proto-Oncogene Proteins c-maf / Q000096:biosynthesis; D018417:Th1 Cells / Q000276:immunology* / Q000637:transplantation; D058504:Th17 Cells / Q000276:immunology*; D018418:Th2 Cells / Q000276:immunology*
chemical_list: D050976:Basic-Leucine Zipper Transcription Factors; D050990:GATA3 Transcription Factor; C494748:Gata3 protein, mouse; D006657:Histones; C556062:IL10 protein, mouse; C495608:Maf protein, mouse; C497441:Nfil3 protein, mouse; D051257:Proto-Oncogene Proteins c-maf; D016753:Interleukin-10; D038362:Glycogen Synthase Kinase 3
keywords: CD4+ T cells; Epigenetic; Glycogen synthase kinase-3; IL-10
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