title: Regulation of NO synthesis, local inflammation, and innate immunity to pathogens by BET family proteins.
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.
authors.affiliation: Max F. Perutz Laboratories, University of Vienna, Vienna, Austria.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Wienerroither
authors.forename: Isabella
authors.initials: I
authors.lastname: Rauch
authors.forename: Felix
authors.initials: F
authors.lastname: Rosebrock
authors.forename: Amanda M
authors.initials: AM
authors.lastname: Jamieson
authors.forename: James
authors.initials: J
authors.lastname: Bradner
authors.forename: Matthias
authors.initials: M
authors.lastname: Muhar
authors.forename: Johannes
authors.initials: J
authors.lastname: Zuber
authors.forename: Mathias
authors.initials: M
authors.lastname: Müller
authors.forename: Thomas
authors.initials: T
authors.lastname: Decker
mesh_terms: D000818:Animals; D001381:Azepines / Q000494:pharmacology; D002478:Cells, Cultured; D002868:Chromosomal Proteins, Non-Histone; D015870:Gene Expression / Q000276:immunology; D054884:Host-Pathogen Interactions / Q000187:drug effects / Q000276:immunology; D007113:Immunity, Innate / Q000235:genetics / Q000276:immunology*; D007249:Inflammation / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D053118:Influenza A Virus, H1N1 Subtype; D008089:Listeria monocytogenes / Q000276:immunology / Q000502:physiology; D008264:Macrophages / Q000276:immunology / Q000378:metabolism / Q000382:microbiology; D051379:Mice; D008810:Mice, Inbred C57BL; D009569:Nitric Oxide / Q000096:biosynthesis / Q000276:immunology*; D052247:Nitric Oxide Synthase Type II / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D009976:Orthomyxoviridae Infections / Q000235:genetics / Q000276:immunology / Q000821:virology; D011401:Promoter Regions, Genetic / Q000235:genetics / Q000276:immunology; D011485:Protein Binding / Q000187:drug effects / Q000276:immunology; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016019:Survival Analysis; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014230:Triazoles / Q000494:pharmacology; D000092468:Bromodomain Containing Proteins
chemical_list: D001381:Azepines; D002868:Chromosomal Proteins, Non-Histone; D009569:Nitric Oxide; D052247:Nitric Oxide Synthase Type II; D009687:Nuclear Proteins; D017346:Protein Serine-Threonine Kinases; D014157:Transcription Factors; D014230:Triazoles; C561695:(+)-JQ1 compound; C490844:Brd2 protein, mouse; D000092468:Bromodomain Containing Proteins; C518476:Brd3 protein, mouse; C486694:Brd4 protein, mouse; C496317:Nos2 protein, mouse