title: CREB, ATF, and AP-1 transcription factors regulate IFN-gamma secretion by human T cells in response to mycobacterial antigen.
abstract: IFN-gamma production by T cells is pivotal for defense against many pathogens, and the proximal promoter of IFN-gamma, -73 to -48 bp upstream of the transcription start site, is essential for its expression. However, transcriptional regulation mechanisms through this promoter in primary human cells remain unclear. We studied the effects of cAMP response element binding protein/activating transcription factor (CREB/ATF) and AP-1 transcription factors on the proximal promoter of IFN-gamma in human T cells stimulated with Mycobacterium tuberculosis. Using EMSA, supershift assays, and promoter pulldown assays, we demonstrated that CREB, ATF-2, and c-Jun, but not cyclic AMP response element modulator, ATF-1, or c-Fos, bind to the proximal promoter of IFN-gamma upon stimulation, and coimmunoprecipitation indicated the possibility of interaction among these transcription factors. Chromatin immunoprecipitation confirmed the recruitment of these transcription factors to the IFN-gamma proximal promoter in live Ag-activated T cells. Inhibition of ATF-2 activity in T cells with a dominant-negative ATF-2 peptide or with small interfering RNA markedly reduced the expression of IFN-gamma and decreased the expression of CREB and c-Jun. These findings suggest that CREB, ATF-2, and c-Jun are recruited to the IFN-gamma proximal promoter and that they up-regulate IFN-gamma transcription in response to microbial Ag. Additionally, ATF-2 controls expression of CREB and c-Jun during T cell activation.
authors.affiliation: Center for Pulmonary and Infectious Disease Control, University of Texas Health Center, Tyler, TX 75708, USA. buka.samten@uthct.edu
authors.forename: Buka
authors.initials: B
authors.lastname: Samten
authors.forename: James C
authors.initials: JC
authors.lastname: Townsend
authors.forename: Steven E
authors.initials: SE
authors.lastname: Weis
authors.forename: Anindita
authors.initials: A
authors.lastname: Bhoumik
authors.forename: Peter
authors.initials: P
authors.lastname: Klucar
authors.forename: Homayoun
authors.initials: H
authors.lastname: Shams
authors.forename: Peter F
authors.initials: PF
authors.lastname: Barnes
mesh_terms: D051698:Activating Transcription Factor 2 / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D000942:Antigens, Bacterial / Q000276:immunology*; D017252:CD3 Complex / Q000276:immunology; D002470:Cell Survival; D002478:Cells, Cultured; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism*; D024202:Electrophoretic Mobility Shift Assay; D006801:Humans; D007371:Interferon-gamma / Q000235:genetics / Q000378:metabolism*; D009169:Mycobacterium tuberculosis / Q000276:immunology; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding; D034741:RNA, Small Interfering / Q000235:genetics; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*; D018808:Transcription Factor AP-1 / Q000378:metabolism*
chemical_list: D051698:Activating Transcription Factor 2; D000942:Antigens, Bacterial; D017252:CD3 Complex; D017362:Cyclic AMP Response Element-Binding Protein; D034741:RNA, Small Interfering; D018808:Transcription Factor AP-1; D007371:Interferon-gamma