tetano
Editor, Senior Moderator
Mol Cell Biol. 2013 Nov 18. [Epub ahead of print]
Regulation of NO synthesis, local inflammation and innate immunity to pathogens by BET family proteins.
Wienerroither S, Rauch I, Rosebrock F, Jamieson AM, Bradner J, Muhar M, Zuber J, M?ller M, Decker T.
Source
Max F. Perutz Laboratories, University of Vienna, Dr. Bohr-Gasse 9, 1030 Vienna, Austria.
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 transcription factors NFκB and the type I interferon-activated ISGF3. Here we show that infection of macrophages with the intracellular bacterial pathogen Listeria monocytogenes (Lm) causes binding of 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 Brd-mediated CTD phosphorylation at serine 5 and the rate of transcriptional re-initiation. Underscoring the critical importance of Brd for the regulation of immune responses, application of JQ1 reduced NO production in mice infected with Lm as well as innate resistance to Lm and influenza virus. In a murine model of inflammatory disease JQ1 treatment increased the colitogenic activity of 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.
PMID:
24248598
[PubMed - as supplied by publisher]
http://www.ncbi.nlm.nih.gov/pubmed/24248598
Regulation of NO synthesis, local inflammation and innate immunity to pathogens by BET family proteins.
Wienerroither S, Rauch I, Rosebrock F, Jamieson AM, Bradner J, Muhar M, Zuber J, M?ller M, Decker T.
Source
Max F. Perutz Laboratories, University of Vienna, Dr. Bohr-Gasse 9, 1030 Vienna, Austria.
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 transcription factors NFκB and the type I interferon-activated ISGF3. Here we show that infection of macrophages with the intracellular bacterial pathogen Listeria monocytogenes (Lm) causes binding of 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 Brd-mediated CTD phosphorylation at serine 5 and the rate of transcriptional re-initiation. Underscoring the critical importance of Brd for the regulation of immune responses, application of JQ1 reduced NO production in mice infected with Lm as well as innate resistance to Lm and influenza virus. In a murine model of inflammatory disease JQ1 treatment increased the colitogenic activity of 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.
PMID:
24248598
[PubMed - as supplied by publisher]
http://www.ncbi.nlm.nih.gov/pubmed/24248598