title: Histone deacetylase 7 promotes Toll-like receptor 4-dependent proinflammatory gene expression in macrophages.
abstract: Broad-spectrum inhibitors of histone deacetylases (HDACs) constrain Toll-like receptor (TLR)-inducible production of key proinflammatory mediators. Here we investigated HDAC-dependent inflammatory responses in mouse macrophages. Of the classical Hdacs, Hdac7 was expressed at elevated levels in inflammatory macrophages (thioglycollate-elicited peritoneal macrophages) as compared with bone marrow-derived macrophages and the RAW264 cell line. Overexpression of a specific, alternatively spliced isoform of Hdac7 lacking the N-terminal 22 amino acids (Hdac7-u), but not the Refseq Hdac7 (Hdac7-s), promoted LPS-inducible expression of Hdac-dependent genes (Edn1, Il-12p40, and Il-6) in RAW264 cells. A novel class IIa-selective HDAC inhibitor reduced recombinant human HDAC7 enzyme activity as well as TLR-induced production of inflammatory mediators in thioglycollate-elicited peritoneal macrophages. Both LPS and Hdac7-u up-regulated the activity of the Edn1 promoter in an HDAC-dependent fashion in RAW264 cells. A hypoxia-inducible factor (HIF) 1 binding site in this promoter was required for HDAC-dependent TLR-inducible promoter activity and for Hdac7- and HIF-1α-mediated trans-activation. Coimmunoprecipitation assays showed that both Hdac7-u and Hdac7-s interacted with HIF-1α, whereas only Hdac7-s interacted with the transcriptional repressor CtBP1. Thus, Hdac7-u positively regulates HIF-1α-dependent TLR signaling in macrophages, whereas an interaction with CtBP1 likely prevents Hdac7-s from exerting this effect. Hdac7 may represent a potential inflammatory disease target.
authors.affiliation: From the Institute for Molecular Bioscience and Australian Infectious Diseases Research Centre, University of Queensland, Queensland 4072, Australia and.
authors.forename: Melanie R
authors.initials: MR
authors.lastname: Shakespear
authors.affiliation: From the Institute for Molecular Bioscience and Australian Infectious Diseases Research Centre, University of Queensland, Queensland 4072, Australia and.
authors.forename: Daniel M
authors.initials: DM
authors.lastname: Hohenhaus
authors.affiliation: From the Institute for Molecular Bioscience and Australian Infectious Diseases Research Centre, University of Queensland, Queensland 4072, Australia and.
authors.forename: Greg M
authors.initials: GM
authors.lastname: Kelly
authors.affiliation: From the Institute for Molecular Bioscience and Australian Infectious Diseases Research Centre, University of Queensland, Queensland 4072, Australia and.
authors.forename: Nabilah A
authors.initials: NA
authors.lastname: Kamal
authors.affiliation: From the Institute for Molecular Bioscience and Australian Infectious Diseases Research Centre, University of Queensland, Queensland 4072, Australia and.
authors.forename: Praveer
authors.initials: P
authors.lastname: Gupta
authors.affiliation: From the Institute for Molecular Bioscience and Australian Infectious Diseases Research Centre, University of Queensland, Queensland 4072, Australia and.
authors.forename: Larisa I
authors.initials: LI
authors.lastname: Labzin
authors.affiliation: From the Institute for Molecular Bioscience and Australian Infectious Diseases Research Centre, University of Queensland, Queensland 4072, Australia and.
authors.forename: Kate
authors.initials: K
authors.lastname: Schroder
authors.affiliation: the Roslin Institute and Royal (Dick) School of Veterinary Studies, University of Edinburgh, Roslin EH25 9PS Scotland, United Kingdom.
authors.forename: Valerie
authors.initials: V
authors.lastname: Garceau
authors.affiliation: From the Institute for Molecular Bioscience and Australian Infectious Diseases Research Centre, University of Queensland, Queensland 4072, Australia and.
authors.forename: Sheila
authors.initials: S
authors.lastname: Barbero
authors.affiliation: From the Institute for Molecular Bioscience and Australian Infectious Diseases Research Centre, University of Queensland, Queensland 4072, Australia and.
authors.forename: Abishek
authors.initials: A
authors.lastname: Iyer
authors.affiliation: the Roslin Institute and Royal (Dick) School of Veterinary Studies, University of Edinburgh, Roslin EH25 9PS Scotland, United Kingdom.
authors.forename: David A
authors.initials: DA
authors.lastname: Hume
authors.affiliation: From the Institute for Molecular Bioscience and Australian Infectious Diseases Research Centre, University of Queensland, Queensland 4072, Australia and.
authors.forename: Robert C
authors.initials: RC
authors.lastname: Reid
authors.affiliation: From the Institute for Molecular Bioscience and Australian Infectious Diseases Research Centre, University of Queensland, Queensland 4072, Australia and.
authors.forename: Katharine M
authors.initials: KM
authors.lastname: Irvine
authors.affiliation: From the Institute for Molecular Bioscience and Australian Infectious Diseases Research Centre, University of Queensland, Queensland 4072, Australia and.
authors.forename: David P
authors.initials: DP
authors.lastname: Fairlie
authors.affiliation: From the Institute for Molecular Bioscience and Australian Infectious Diseases Research Centre, University of Queensland, Queensland 4072, Australia and. Electronic address: m.sweet@imb.uq.edu.au.
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Sweet
mesh_terms: D000429:Alcohol Oxidoreductases / Q000235:genetics / Q000378:metabolism; D000818:Animals; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation; D057809:HEK293 Cells; D006655:Histone Deacetylases / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism; D007249:Inflammation / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D008070:Lipopolysaccharides / Q000494:pharmacology; D008264:Macrophages / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D051197:Toll-Like Receptor 4 / Q000819:agonists / Q000235:genetics / Q000378:metabolism*
chemical_list: D004268:DNA-Binding Proteins; C497442:HIF1A protein, human; C497443:Hif1a protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D008070:Lipopolysaccharides; C495345:TLR4 protein, human; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D000429:Alcohol Oxidoreductases; C096794:C-terminal binding protein; C543273:HDAC7 protein, human; C543274:Hdac7 protein, mouse; D006655:Histone Deacetylases
keywords: Histone Deacetylase; Hypoxia-inducible Factor (HIF); Inflammation; Macrophages; Toll-like Receptor (TLR)