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

J Immunol. 2005 May 1;174(9):5687-94. doi: 10.4049/jimmunol.174.9.5687.

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.

Publication types

  • Comparative Study
  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Acetylation
  • CREB-Binding Protein
  • Cell Line, Tumor
  • DNA-Binding Proteins / biosynthesis
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism
  • Enzyme Inhibitors / pharmacology
  • Gene Expression Regulation / immunology*
  • Gene Silencing / immunology
  • HLA-DR Antigens / biosynthesis
  • HLA-DR Antigens / genetics*
  • Histone Deacetylase Inhibitors
  • Histone Deacetylases / biosynthesis*
  • Histone Deacetylases / genetics
  • Humans
  • Interferon Regulatory Factor-1
  • Interferon-gamma / antagonists & inhibitors*
  • Interferon-gamma / physiology
  • Macrophage Activation / immunology
  • Membrane Glycoproteins / agonists
  • Membrane Glycoproteins / physiology
  • Monocytes / immunology*
  • Monocytes / metabolism
  • Monocytes / microbiology
  • Multiprotein Complexes / physiology
  • Mycobacterium avium / immunology*
  • Mycobacterium tuberculosis / immunology*
  • Nuclear Proteins / antagonists & inhibitors
  • Nuclear Proteins / biosynthesis
  • Nuclear Proteins / genetics
  • Nuclear Proteins / physiology
  • Phosphoproteins / biosynthesis
  • Phosphoproteins / genetics
  • Phosphorylation
  • Receptors, Cell Surface / agonists
  • Receptors, Cell Surface / physiology
  • Repressor Proteins / biosynthesis
  • Repressor Proteins / genetics
  • STAT1 Transcription Factor
  • Toll-Like Receptor 2
  • Toll-Like Receptors
  • Trans-Activators / antagonists & inhibitors
  • Trans-Activators / biosynthesis
  • Trans-Activators / genetics
  • Trans-Activators / metabolism
  • Trans-Activators / physiology
  • Tyrosine / metabolism
  • Up-Regulation / genetics
  • Up-Regulation / immunology*

Substances

  • DNA-Binding Proteins
  • Enzyme Inhibitors
  • HLA-DR Antigens
  • Histone Deacetylase Inhibitors
  • IRF1 protein, human
  • Interferon Regulatory Factor-1
  • MHC class II transactivator protein
  • Membrane Glycoproteins
  • Multiprotein Complexes
  • Nuclear Proteins
  • Phosphoproteins
  • Receptors, Cell Surface
  • Repressor Proteins
  • SIN3A transcription factor
  • STAT1 Transcription Factor
  • STAT1 protein, human
  • TLR2 protein, human
  • Toll-Like Receptor 2
  • Toll-Like Receptors
  • Trans-Activators
  • Tyrosine
  • Interferon-gamma
  • CREB-Binding Protein
  • CREBBP protein, human
  • Histone Deacetylases