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Modulation of IFN‐γ‐induced gene expression by TLR2 signaling in macrophages is mediated by an NF‐κB‐dependent mechanism
Author(s) -
Benson Sarah,
Grabenstein Jens,
Ernst Joel
Publication year - 2008
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.22.1_supplement.675.8
Subject(s) - tlr2 , ciita , histone deacetylase , signal transduction , chemistry , microbiology and biotechnology , cancer research , gene expression , histone , histone h3 , biology , gene , immune system , immunology , biochemistry , t cell , tlr4 , mhc class ii
Mycobacterium tuberculosis (Mtb) uses multiple mechanisms to avoid destruction by the immune system. We have previously shown that Mtb can inhibit selected macrophage responses to IFN‐γ using TLR2‐dependent and –independent mechanisms. To address the role of TLR2 signaling in mediating this inhibition, we used microarray analysis to identify IFN‐γ‐inducible genes whose expression decreased when macrophages were treated with the specific TLR2/1 ligand Pam 3 CSK 4 (Pam). Four of the genes identified—Ciita, Klrk1, Dnase1l3, and Cxcl11—were further characterized. Ciita and Klrk1 induction by IFN‐γ was rapidly inhibited by Pam while Dnase1l3 and Cxcl11 required prolonged Pam pretreatment prior to IFN‐γ. Histone H4 acetylation at the Ciita and Klrk1 promoters was reduced in macrophages treated simultaneously with Pam and IFN‐γ compared to those treated with IFN‐γ alone. This effect was dependent on histone deacetylase activity. Treatment with the NF‐κB inhibitor parthenolide restored IFN‐γ‐induced gene expression and histone H4 acetylation at the promoters of selected Pam‐inhibited genes including Klrk1 and Cxcl11. These results indicate that TLR2‐dependent inhibition of IFN‐γ‐induced gene expression by Mtb depends on the length of exposure to a TLR2 agonist, is mediated by a mechanism affecting chromatin remodeling, and involves multiple signaling pathways including NF‐κB. NIH‐R01‐AI46097