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Mycobacteria Inhibition of IFN- Induced HLA-DR Gene Expression by Up-Regulating Histone Deacetylation at the Promoter Region in Human THP-1 Monocytic Cells¹

Yue Wang^*, Heather M. Curry^*, Bruce S. Zwilling and William P. Lafuse^2,*

Departments of ^* Molecular Virology, Immunology, and Medical Genetics and Microbiology, Ohio State University, Columbus, OH 43210

Infection of macrophages with mycobacteria has been shown to inhibit the macrophage response to IFN-. In the current study, we examined the effect of Mycobacteria avium, Mycobacteria tuberculosis, and TLR2 stimulation on IFN--induced gene expression in human PMA-differentiated THP-1 monocytic cells. Mycobacterial infection inhibited IFN--induced expression of HLA-DR and HLA-DR 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-DR and HLA-DR mRNA in response to IFN-. Histone acetylation induced by IFN- at the HLA-DR 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-DR promoter in M. avium-infected THP-1 cells stimulated with IFN-. 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.

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