Mycobacterium tuberculosis 19-kDa lipoprotein inhibits IFN-γ-induced chromatin remodeling of MHC2TA by TLR2 and MAPK signaling

Meghan E. Pennini, Rish Pai, David C. Schultz, W. Henry Boom, Clifford V. Harding

Research output: Contribution to journalArticle

135 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)4323-4330
Number of pages8
JournalJournal of Immunology
Volume176
Issue number7
StatePublished - Apr 1 2006
Externally publishedYes

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Chromatin Assembly and Disassembly
Mycobacterium tuberculosis
Lipoproteins
Histones
Acetylation
Macrophages
MHC class II transactivator protein
Genes
Immune Evasion
Chromatin Immunoprecipitation
p38 Mitogen-Activated Protein Kinases

ASJC Scopus subject areas

  • Immunology

Cite this

Mycobacterium tuberculosis 19-kDa lipoprotein inhibits IFN-γ-induced chromatin remodeling of MHC2TA by TLR2 and MAPK signaling. / Pennini, Meghan E.; Pai, Rish; Schultz, David C.; Boom, W. Henry; Harding, Clifford V.

In: Journal of Immunology, Vol. 176, No. 7, 01.04.2006, p. 4323-4330.

Research output: Contribution to journalArticle

Pennini, Meghan E. ; Pai, Rish ; Schultz, David C. ; Boom, W. Henry ; Harding, Clifford V. / Mycobacterium tuberculosis 19-kDa lipoprotein inhibits IFN-γ-induced chromatin remodeling of MHC2TA by TLR2 and MAPK signaling. In: Journal of Immunology. 2006 ; Vol. 176, No. 7. pp. 4323-4330.
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