title: MHC class II transactivator represses human IL-4 gene transcription by interruption of promoter binding with CBP/p300, STAT6 and NFAT1 via histone hypoacetylation.
abstract: In addition to its property of enhancing major histocompatibility complex (MHC) class II expression, the class II transactivator (CIITA) was recently demonstrated to be involved in T helper type 1/type 2 (Th1/Th2) differentiation by regulating interleukin-4 (IL-4) gene transcription. There was however, controversy regarding whether CIITA promotes or suppresses IL-4 expression in the experiments with transgenic mice. To clarify the discrepancy by using simpler experimental systems, human Jurkat T cells that express IL-4 but not interferon-gamma, even if stimulated with phorbol 12-myristate 13-acetate plus ionomycin, were used for CIITA transfection. Significant suppression of IL-4 gene expression was demonstrated. Simultaneously, histones H3 and H4 in the IL-4 promoter were hypoacetylated. The suppression could be totally reversed by the histone deacetylatase inhibitor trichostatin A. Furthermore, the IL-4 expression was determined in primarily established human Th1/Th2 cells to which CIITA small interference RNA (siRNA) had been introduced. A substantially increased level of IL-4 was recorded in the CIITA siRNA-transfected Th1 cells, which was in parallel with significantly enhanced acetylation in histone H3 of the IL-4 promoter. Chromatin immunoprecipitation analysis indicated that CIITA abrogated the binding of coactivator CBP/p300 and transcription factors STAT6/NFAT1 to IL-4 promoter in the CIITA-transfected cells. In conclusion, CIITA was active in the repression of transcription activation of human IL-4 gene in both the T-cell line and the primary human CD4 T cells by preventing transcription factors from binding to IL-4 promoter through histone hypoacetylation. Our data confirm a potential significant role of CIITA in controlling Th1/Th2 differentiation via modulation of IL-4 gene activation.
authors.affiliation: Shanghai Institute of Immunology, Shanghai Jiaotong University School of Medicine, Shanghai, China.
authors.forename: Xiaorong
authors.initials: X
authors.lastname: Zhou
authors.forename: Yang
authors.initials: Y
authors.lastname: Jiang
authors.forename: Liming
authors.initials: L
authors.lastname: Lu
authors.forename: Qing
authors.initials: Q
authors.lastname: Ding
authors.forename: Zhijun
authors.initials: Z
authors.lastname: Jiao
authors.forename: Yun
authors.initials: Y
authors.lastname: Zhou
authors.forename: Lijun
authors.initials: L
authors.lastname: Xin
authors.forename: Kuang-Yen
authors.initials: KY
authors.lastname: Chou
mesh_terms: D000107:Acetylation; D005786:Gene Expression Regulation / Q000235:genetics / Q000276:immunology*; D006684:HLA-DR Antigens / Q000378:metabolism; D006657:Histones / Q000378:metabolism*; D006801:Humans; D015847:Interleukin-4 / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism; D019169:Jurkat Cells; D050778:NFATC Transcription Factors / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics* / Q000276:immunology; D011401:Promoter Regions, Genetic / Q000235:genetics / Q000276:immunology; D034741:RNA, Small Interfering / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D050800:STAT6 Transcription Factor / Q000378:metabolism; D018417:Th1 Cells / Q000276:immunology; D015534:Trans-Activators / Q000235:genetics* / Q000276:immunology; D014158:Transcription, Genetic / Q000276:immunology; D015533:Transcriptional Activation; D014162:Transfection; D050880:p300-CBP Transcription Factors / Q000378:metabolism
chemical_list: D006684:HLA-DR Antigens; D006657:Histones; C083728:MHC class II transactivator protein; D050778:NFATC Transcription Factors; C494006:NFATC2 protein, human; D009687:Nuclear Proteins; D034741:RNA, Small Interfering; D050800:STAT6 Transcription Factor; C494101:STAT6 protein, human; D015534:Trans-Activators; D015847:Interleukin-4; D050880:p300-CBP Transcription Factors