title: Mycobacteria inhibition of IFN-gamma induced HLA-DR gene expression by up-regulating histone deacetylation at the promoter region in human THP-1 monocytic cells.
abstract: Infection of macrophages with mycobacteria has been shown to inhibit the macrophage response to IFN-gamma. In the current study, we examined the effect of Mycobacteria avium, Mycobacteria tuberculosis, and TLR2 stimulation on IFN-gamma-induced gene expression in human PMA-differentiated THP-1 monocytic cells. Mycobacterial infection inhibited IFN-gamma-induced expression of HLA-DRalpha and HLA-DRbeta mRNA and partially inhibited CIITA expression but did not affect expression of IFN regulatory factor-1 mRNA. To determine whether inhibition of histone deacetylase (HDAC) activity could rescue HLA-DR gene expression, butyric acid and MS-275, inhibitors of HDAC activity, were added at the time of M. avium or M. tuberculosis infection or TLR2 stimulation. HDAC inhibition restored the ability of these cells to express HLA-DRalpha and HLA-DRbeta mRNA in response to IFN-gamma. Histone acetylation induced by IFN-gamma at the HLA-DRalpha promoter was repressed upon mycobacteria infection or TLR2 stimulation. HDAC gene expression was not affected by mycobacterial infection. However, mycobacterial infection or TLR2 stimulation up-regulated expression of mammalian Sin3A, a corepressor that is required for MHC class II repression by HDAC. Furthermore, we show that the mammalian Sin3A corepressor is associated with the HLA-DRalpha promoter in M. avium-infected THP-1 cells stimulated with IFN-gamma. Thus, mycobacterial infection of human THP-1 cells specifically inhibits HLA-DR gene expression by a novel pathway that involves HDAC complex formation at the HLA-DR promoter, resulting in histone deacetylation and gene silencing.
authors.affiliation: Department of Molecular Virology, Ohio State University, Columbus, OH 43210, USA.
authors.forename: Yue
authors.initials: Y
authors.lastname: Wang
authors.forename: Heather M
authors.initials: HM
authors.lastname: Curry
authors.forename: Bruce S
authors.initials: BS
authors.lastname: Zwilling
authors.forename: William P
authors.initials: WP
authors.lastname: Lafuse
mesh_terms: D000107:Acetylation; D050882:CREB-Binding Protein; D045744:Cell Line, Tumor; D004268:DNA-Binding Proteins / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000276:immunology*; D020868:Gene Silencing / Q000276:immunology; D006684:HLA-DR Antigens / Q000096:biosynthesis / Q000235:genetics*; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases / Q000096:biosynthesis* / Q000235:genetics; D006801:Humans; D050856:Interferon Regulatory Factor-1; D007371:Interferon-gamma / Q000037:antagonists & inhibitors* / Q000502:physiology; D008262:Macrophage Activation / Q000276:immunology; D008562:Membrane Glycoproteins / Q000819:agonists / Q000502:physiology; D009000:Monocytes / Q000276:immunology* / Q000378:metabolism / Q000382:microbiology; D046912:Multiprotein Complexes / Q000502:physiology; D009162:Mycobacterium avium / Q000276:immunology*; D009169:Mycobacterium tuberculosis / Q000276:immunology*; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology; D010750:Phosphoproteins / Q000096:biosynthesis / Q000235:genetics; D010766:Phosphorylation; D011956:Receptors, Cell Surface / Q000819:agonists / Q000502:physiology; D012097:Repressor Proteins / Q000096:biosynthesis / Q000235:genetics; D050794:STAT1 Transcription Factor; D056264:Sin3 Histone Deacetylase and Corepressor Complex; D051195:Toll-Like Receptor 2; D051193:Toll-Like Receptors; D015534:Trans-Activators / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D014443:Tyrosine / Q000378:metabolism; D015854:Up-Regulation / Q000235:genetics / Q000276:immunology*
chemical_list: D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; D006684:HLA-DR Antigens; D056572:Histone Deacetylase Inhibitors; C494257:IRF1 protein, human; D050856:Interferon Regulatory Factor-1; C083728:MHC class II transactivator protein; D008562:Membrane Glycoproteins; D046912:Multiprotein Complexes; D009687:Nuclear Proteins; D010750:Phosphoproteins; D011956:Receptors, Cell Surface; D012097:Repressor Proteins; C099683:SIN3A transcription factor; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; C495342:TLR2 protein, human; D051195:Toll-Like Receptor 2; D051193:Toll-Like Receptors; D015534:Trans-Activators; D014443:Tyrosine; D007371:Interferon-gamma; D050882:CREB-Binding Protein; C494363:CREBBP protein, human; D006655:Histone Deacetylases; D056264:Sin3 Histone Deacetylase and Corepressor Complex