title: BET bromodomain inhibition suppresses transcriptional responses to cytokine-Jak-STAT signaling in a gene-specific manner in human monocytes.
abstract: Disruption of the interaction of bromo and extraterminal (BET) proteins with acetylated histones using small molecule inhibitors suppresses Myc-driven cancers and TLR-induced inflammation in mouse models. The predominant mechanism of BET inhibitor action is to suppress BET-mediated recruitment of positive transcription elongation factor b and, thus, transcription elongation. We investigated the effects of BET inhibitor I-BET151 on transcriptional responses to TLR4 and TNF in primary human monocytes and also on responses to cytokines IFN-β, IFN-γ, IL-4, and IL-10, which activate the JAK-STAT signaling pathway and are important for monocyte polarization and inflammatory diseases. I-BET151 suppressed TLR4- and TNF-induced IFN responses by diminishing both autocrine IFN-β expression and transcriptional responses to IFN-β. I-BET151 inhibited cytokine-induced transcription of STAT targets in a gene-specific manner without affecting STAT activation or recruitment. This inhibition was independent of Myc or other upstream activators. IFN-stimulated gene transcription is regulated primarily at the level of transcription initiation. Accordingly, we found that I-BET151 suppressed the recruitment of transcriptional machinery to the CXCL10 promoter and an upstream enhancer. Our findings suggest that BET inhibition reduces inflammation partially through suppressing cytokine activity and expands the understanding of the inhibitory and potentially selective immunosuppressive effects of inhibiting BET proteins.
authors.affiliation: Arthritis and Tissue Degeneration Program and David Z. Rosensweig Center for Genomics Research, Hospital for Special Surgery, New York, New York, USA.
authors.forename: Chun Hin
authors.initials: CH
authors.lastname: Chan
authors.affiliation: Arthritis and Tissue Degeneration Program and David Z. Rosensweig Center for Genomics Research, Hospital for Special Surgery, New York, New York, USA.
authors.forename: Celestia
authors.initials: C
authors.lastname: Fang
authors.affiliation: Arthritis and Tissue Degeneration Program and David Z. Rosensweig Center for Genomics Research, Hospital for Special Surgery, New York, New York, USA.
authors.forename: Anna
authors.initials: A
authors.lastname: Yarilina
authors.affiliation: GlaxoSmithKline, Epinova DPU, Stevenage, United Kingdom.
authors.forename: Rab K
authors.initials: RK
authors.lastname: Prinjha
authors.affiliation: Arthritis and Tissue Degeneration Program and David Z. Rosensweig Center for Genomics Research, Hospital for Special Surgery, New York, New York, USA.
authors.forename: Yu
authors.initials: Y
authors.lastname: Qiao
authors.affiliation: Arthritis and Tissue Degeneration Program and David Z. Rosensweig Center for Genomics Research, Hospital for Special Surgery, New York, New York, USA.|Graduate Program in Immunology and Microbial Pathogenesis, Weill Cornell Graduate School of Medical Sciences, New York, New York, USA.
authors.forename: Lionel B
authors.initials: LB
authors.lastname: Ivashkiv
mesh_terms: D002454:Cell Differentiation; D054357:Chemokine CXCL10 / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000276:immunology; D005786:Gene Expression Regulation; D006576:Heterocyclic Compounds, 4 or More Rings / Q000494:pharmacology*; D006801:Humans; D016899:Interferon-beta / Q000235:genetics / Q000276:immunology; D007371:Interferon-gamma / Q000235:genetics / Q000276:immunology; D016753:Interleukin-10 / Q000235:genetics / Q000276:immunology; D015847:Interleukin-4 / Q000235:genetics / Q000276:immunology; D053612:Janus Kinases / Q000235:genetics* / Q000276:immunology; D008264:Macrophages / Q000166:cytology / Q000187:drug effects* / Q000276:immunology; D009000:Monocytes / Q000166:cytology / Q000187:drug effects* / Q000276:immunology; D010766:Phosphorylation; D061251:Primary Cell Culture; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000276:immunology; D050791:STAT Transcription Factors / Q000235:genetics* / Q000276:immunology; D015398:Signal Transduction
chemical_list: C114753:CXCL10 protein, human; D054357:Chemokine CXCL10; C568713:GSK1210151A; D006576:Heterocyclic Compounds, 4 or More Rings; C508609:IL10 protein, human; C508598:IL4 protein, human; D050791:STAT Transcription Factors; D016753:Interleukin-10; D015847:Interleukin-4; D016899:Interferon-beta; D007371:Interferon-gamma; D053612:Janus Kinases; D017346:Protein Serine-Threonine Kinases
keywords: Chromatin remodeling; Cytokines; Inflammation; Monocytes; Transcription