Regulation of NO synthesis, local inflammation, and innate: Immunity to pathogens by BET family proteins

Sebastian Wienerroither, Isabella Rauch, Felix Rosebrock, Amanda M. Jamieson, James Bradner, Matthias Muhar, Johannes Zuber, Mathias Müller, Thomas Decker

Research output: Contribution to journalArticle

36 Citations (Scopus)

Abstract

Transcriptional activation of the Nos2 gene, encoding inducible nitric oxide synthase (iNOS), during infection or inflammation requires coordinate assembly of an initiation complex by the transcription factors NF-κB and type I interferon-activated ISGF3. Here we show that infection of macrophages with the intracellular bacterial pathogen Listeria monocytogenes caused binding of the BET proteins Brd2, Brd3, and, most prominently, Brd4 to the Nos2 promoter and that a profound reduction of Nos2 expression occurred in the presence of the BET inhibitor JQ1. RNA polymerase activity at the Nos2 gene was regulated through Brdmediated C-terminal domain (CTD) phosphorylation at serine 5. Underscoring the critical importance of Brd for the regulation of immune responses, application of JQ1 reduced NO production in mice infected with L. monocytogenes, as well as innate resistance to L. monocytogenes and influenza virus. In a murine model of inflammatory disease, JQ1 treatment increased the colitogenic activity of dextran sodium sulfate (DSS). The data presented in our study suggest that BET protein inhibition in a clinical setting poses the risk of altering the innate immune response to infectious or inflammatory challenge.

Original languageEnglish (US)
Pages (from-to)415-427
Number of pages13
JournalMolecular and Cellular Biology
Volume34
Issue number3
DOIs
StatePublished - Feb 1 2014
Externally publishedYes

Fingerprint

Listeria monocytogenes
Innate Immunity
Inflammation
Interferon Type I
Dextran Sulfate
Proteins
Nitric Oxide Synthase Type II
DNA-Directed RNA Polymerases
Infection
Orthomyxoviridae
Serine
Transcriptional Activation
Genes
Carrier Proteins
Transcription Factors
Macrophages
Phosphorylation

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

Cite this

Regulation of NO synthesis, local inflammation, and innate : Immunity to pathogens by BET family proteins. / Wienerroither, Sebastian; Rauch, Isabella; Rosebrock, Felix; Jamieson, Amanda M.; Bradner, James; Muhar, Matthias; Zuber, Johannes; Müller, Mathias; Decker, Thomas.

In: Molecular and Cellular Biology, Vol. 34, No. 3, 01.02.2014, p. 415-427.

Research output: Contribution to journalArticle

Wienerroither, S, Rauch, I, Rosebrock, F, Jamieson, AM, Bradner, J, Muhar, M, Zuber, J, Müller, M & Decker, T 2014, 'Regulation of NO synthesis, local inflammation, and innate: Immunity to pathogens by BET family proteins', Molecular and Cellular Biology, vol. 34, no. 3, pp. 415-427. https://doi.org/10.1128/MCB.01353-13
Wienerroither, Sebastian ; Rauch, Isabella ; Rosebrock, Felix ; Jamieson, Amanda M. ; Bradner, James ; Muhar, Matthias ; Zuber, Johannes ; Müller, Mathias ; Decker, Thomas. / Regulation of NO synthesis, local inflammation, and innate : Immunity to pathogens by BET family proteins. In: Molecular and Cellular Biology. 2014 ; Vol. 34, No. 3. pp. 415-427.
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