Journal
JOURNAL OF IMMUNOLOGY
Volume 174, Issue 9, Pages 5687-5694Publisher
AMER ASSOC IMMUNOLOGISTS
DOI: 10.4049/jimmunol.174.9.5687
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- NIAID NIH HHS [AI45673] Funding Source: Medline
- NIDDK NIH HHS [DK57667] Funding Source: Medline
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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-DR alpha and HLA-DR beta 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 NIS-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-DRa and HLA-DRO mRNA in response to IFN-gamma. Histone acetylation induced by IFN-gamma at the HLA-DRa 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 11 repression by HDAC. Furthermore, we show that the mammalian Sin3A corepressor is associated with the HLA-DRa promoter in M. avium-infected THP-1 cells stimulated with IFN-gamma. Thus, mycobacterial infection of human THP-I 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. The Journal of Immunology, 2005.
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