Mycobacteria Inhibition of IFN-γ 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-γ. In the current study, we examined the effect of Mycobacteria avium, Mycobacteria tuberculosis, and TLR2 stimulation on IFN-γ-induced gene expression in human PMA-differentiated THP-1 monocytic cells. Mycobacterial infection inhibited IFN-γ-induced expression of HLA-DRα and HLA-DRβ 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-DRα and HLA-DRβ mRNA in response to IFN-γ. Histone acetylation induced by IFN-γ at the HLA-DRα 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-DRα promoter in M. avium-infected THP-1 cells stimulated with IFN-γ. 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.

Suppression of TLR2-Induced IL-12, Reactive Oxygen Species, and Inducible Nitric Oxide Synthase Expression byMycobacterium tuberculosisAntigens Expressed inside Macrophages during the Course of Infection

“…tuberculosis is known to downmodulate the expression of MHC class II expression on infected macrophages early in the infection process (37). We show in this article that Ags expressed early during the infection contribute toward this downmodulation and, for the first time, present data that this modulation continues later in the infection with the expression of day-5 Ags.…”

Proteome Analysis of Coinfection of Epithelial Cells with Filifactor alocis and Porphyromonas gingivalis Shows Modulation of Pathogen and Host Regulatory Pathways

“…Bacterially induced DNA methylation was shown earlier to affect the host cell proliferation (64). While host-pathogen methyltransferase similarities among many virulent strains of bacteria were noticed earlier (65), chromatin modification through bacterial proteins can regulate expression of host genes and enzymes such as histone deacetylase (HDAC) (66). Such DNA methylation and histone acetylation are commonly associated with cancer and tumor growth (59).…”

Mycobacterium bovis BCG Attenuates Surface Expression of Mature Class II Molecules through IL-10-Dependent Inhibition of Cathepsin S

“…For example, using the RAW 264.7 mouse macrophage cell line infected with M. avium as a model, reduced surface expression of class II proteins was shown to be associated with inhibition of IFN-␥ signaling and STAT-1 phosphorylation and MHC class II gene expression (45). Recently, inhibition of class II gene expression in macrophages infected with virulent Mtb was recently shown to involve histone deacetylase complex formation at the HLA-DR promoter, resulting in histone deacetylation and gene silencing (46).…”