TY - JOUR
T1 - Mycobacterium tuberculosis 19-kDa lipoprotein inhibits IFN-γ-induced chromatin remodeling of MHC2TA by TLR2 and MAPK signaling
AU - Pennini, Meghan E.
AU - Pai, Rish K.
AU - Schultz, David C.
AU - Boom, W. Henry
AU - Harding, Clifford V.
PY - 2006/4/1
Y1 - 2006/4/1
N2 - During infection of macrophages, prolonged signaling by Mycobacterium tuberculosis (Mtb) or its 19-kDa lipoprotein (LpqH; Rv3763) inhibits IFN-γ-induced expression of several immune function genes, including class II transactivator (CIITA), which regulates class II MHC. Mtb does not inhibit early IFN-γ signaling events, e.g., Stat1α activation. This study analyzed downstream mechanisms that regulate the transcription of MHC2TA, the gene encoding CIITA. Chromatin immunoprecipitation showed that IFN-α induced acetylation of histones H3 and H4 at the CIITA promoter IV (pIV). In contrast, IFN-γ-dependent histone acetylation at CIITA pIV was inhibited by Mtb or 19-kDa lipoprotein. Mtb 19-kDa lipoprotein also inhibited IFN-γ-dependent recruitment of Brahma-related gene 1, a chromatin remodeling protein, to CIITA pIV. Mtb 19-kDa lipoprotein did not inhibit histone acetylation in TLR2-/- macrophages. Furthermore, 19-kDa lipoprotein did not inhibit CIITA expression or IFN-γ-dependent histone acetylation of CIITA pIV in macrophages treated with inhibitors of MAPKs p38 or ERK. Thus, CIITA expression was inhibited by TLR2-induced MAPK signaling that caused histone hypoacetylation at CIITA pIV and suppression of CIITA transcription. Chromatin remodeling at MHC2TA is a novel target of inhibition by Mtb. These mechanisms may diminish class II MHC expression by infected macrophages, contributing to immune evasion by Mtb.
AB - During infection of macrophages, prolonged signaling by Mycobacterium tuberculosis (Mtb) or its 19-kDa lipoprotein (LpqH; Rv3763) inhibits IFN-γ-induced expression of several immune function genes, including class II transactivator (CIITA), which regulates class II MHC. Mtb does not inhibit early IFN-γ signaling events, e.g., Stat1α activation. This study analyzed downstream mechanisms that regulate the transcription of MHC2TA, the gene encoding CIITA. Chromatin immunoprecipitation showed that IFN-α induced acetylation of histones H3 and H4 at the CIITA promoter IV (pIV). In contrast, IFN-γ-dependent histone acetylation at CIITA pIV was inhibited by Mtb or 19-kDa lipoprotein. Mtb 19-kDa lipoprotein also inhibited IFN-γ-dependent recruitment of Brahma-related gene 1, a chromatin remodeling protein, to CIITA pIV. Mtb 19-kDa lipoprotein did not inhibit histone acetylation in TLR2-/- macrophages. Furthermore, 19-kDa lipoprotein did not inhibit CIITA expression or IFN-γ-dependent histone acetylation of CIITA pIV in macrophages treated with inhibitors of MAPKs p38 or ERK. Thus, CIITA expression was inhibited by TLR2-induced MAPK signaling that caused histone hypoacetylation at CIITA pIV and suppression of CIITA transcription. Chromatin remodeling at MHC2TA is a novel target of inhibition by Mtb. These mechanisms may diminish class II MHC expression by infected macrophages, contributing to immune evasion by Mtb.
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U2 - 10.4049/jimmunol.176.7.4323
DO - 10.4049/jimmunol.176.7.4323
M3 - Article
C2 - 16547269
AN - SCOPUS:33646039385
SN - 0022-1767
VL - 176
SP - 4323
EP - 4330
JO - Journal of Immunology
JF - Journal of Immunology
IS - 7
ER -