Article ; Online: Regulation of NO synthesis, local inflammation, and innate immunity to pathogens by BET family proteins.
Molecular and cellular biology
2013 Volume 34, Issue 3, Page(s) 415–427
Abstract: ... with the intracellular bacterial pathogen Listeria monocytogenes caused binding of the BET proteins Brd2, Brd3, and, most ... 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 ...
| 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 Brd-mediated 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. |
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| MeSH term(s) | Animals ; Azepines/pharmacology ; Cells, Cultured ; Chromosomal Proteins, Non-Histone ; Gene Expression/immunology ; Host-Pathogen Interactions/drug effects ; Host-Pathogen Interactions/immunology ; Immunity, Innate/genetics ; Immunity, Innate/immunology ; Inflammation/genetics ; Inflammation/immunology ; Inflammation/metabolism ; Influenza A Virus, H1N1 Subtype ; Listeria monocytogenes/immunology ; Listeria monocytogenes/physiology ; Macrophages/immunology ; Macrophages/metabolism ; Macrophages/microbiology ; Mice ; Mice, Inbred C57BL ; Nitric Oxide/biosynthesis ; Nitric Oxide/immunology ; Nitric Oxide Synthase Type II/genetics ; Nitric Oxide Synthase Type II/immunology ; Nitric Oxide Synthase Type II/metabolism ; Nuclear Proteins/genetics ; Nuclear Proteins/metabolism ; Orthomyxoviridae Infections/genetics ; Orthomyxoviridae Infections/immunology ; Orthomyxoviridae Infections/virology ; Promoter Regions, Genetic/genetics ; Promoter Regions, Genetic/immunology ; Protein Binding/drug effects ; Protein Binding/immunology ; Protein Serine-Threonine Kinases/genetics ; Protein Serine-Threonine Kinases/metabolism ; RNA Interference ; Reverse Transcriptase Polymerase Chain Reaction ; Survival Analysis ; Transcription Factors/genetics ; Transcription Factors/metabolism ; Triazoles/pharmacology |
| Chemical Substances | (+)-JQ1 compound ; Azepines ; Brd2 protein, mouse ; Brd3 protein, mouse ; Brd4 protein, mouse ; Chromosomal Proteins, Non-Histone ; Nuclear Proteins ; Transcription Factors ; Triazoles ; Nitric Oxide (31C4KY9ESH) ; Nitric Oxide Synthase Type II (EC 1.14.13.39) ; Nos2 protein, mouse (EC 1.14.13.39) ; Protein Serine-Threonine Kinases (EC 2.7.11.1) |
| Language | English |
| Publishing date | 2013-11-18 |
| Publishing country | United States |
| Document type | Journal Article ; Research Support, Non-U.S. Gov't |
| ZDB-ID | 779397-2 |
| ISSN | 1098-5549 ; 0270-7306 |
| ISSN (online) | 1098-5549 |
| ISSN | 0270-7306 |
| DOI | 10.1128/MCB.01353-13 |
| Database | MEDical Literature Analysis and Retrieval System OnLINE |
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