title: Histone deacetylase 3 regulates the inflammatory gene expression programme of rheumatoid arthritis fibroblast-like synoviocytes.
abstract: OBJECTIVE
  Non-selective histone deacetylase (HDAC) inhibitors (HDACi) have demonstrated anti-inflammatory properties in both in vitro and in vivo models of rheumatoid arthritis (RA). Here, we investigated the potential contribution of specific class I and class IIb HDACs to inflammatory gene expression in RA fibroblast-like synoviocytes (FLS).
  
  
  METHODS
  RA FLS were incubated with pan-HDACi (ITF2357, givinostat) or selective HDAC1/2i, HDAC3/6i, HDAC6i and HDAC8i. Alternatively, FLS were transfected with HDAC3, HDAC6 or interferon (IFN)-α/β receptor alpha chain (IFNAR1) siRNA. mRNA expression of interleukin (IL)-1β-inducible genes was measured by quantitative PCR (qPCR) array and signalling pathway activation by immunoblotting and DNA-binding assays.
  
  
  RESULTS
  HDAC3/6i, but not HDAC1/2i and HDAC8i, significantly suppressed the majority of IL-1β-inducible genes targeted by pan-HDACi in RA FLS. Silencing of HDAC3 expression reproduced the effects of HDAC3/6i on gene regulation, contrary to HDAC6-specific inhibition and HDAC6 silencing. Screening of the candidate signal transducers and activators of transcription (STAT)1 transcription factor revealed that HDAC3/6i abrogated STAT1 Tyr701 phosphorylation and DNA binding, but did not affect STAT1 acetylation. HDAC3 activity was required for type I IFN production and subsequent STAT1 activation in FLS. Suppression of type I IFN release by HDAC3/6i resulted in reduced expression of a subset of IFN-dependent genes, including the chemokines CXCL9 and CXCL11.
  
  
  CONCLUSIONS
  Inhibition of HDAC3 in RA FLS largely recapitulates the effects of pan-HDACi in suppressing inflammatory gene expression, including type I IFN production in RA FLS. Our results identify HDAC3 as a potential therapeutic target in the treatment of RA and type I IFN-driven autoimmune diseases.
authors.affiliation: Department of Experimental Immunology and Department of Clinical Immunology and Rheumatology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.|Laboratory of Translational Immunology and Department of Rheumatology and Clinical Immunology, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Chiara
authors.initials: C
authors.lastname: Angiolilli
authors.affiliation: Department of Experimental Immunology and Department of Clinical Immunology and Rheumatology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.|Laboratory of Translational Immunology and Department of Rheumatology and Clinical Immunology, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Pawel A
authors.initials: PA
authors.lastname: Kabala
authors.affiliation: Department of Experimental Immunology and Department of Clinical Immunology and Rheumatology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.|Manchester Collaborative Centre for Inflammation Research, The University of Manchester, Manchester, UK.
authors.forename: Aleksander M
authors.identifier: http://orcid.org/0000-0001-9472-850X
authors.initials: AM
authors.lastname: Grabiec
authors.affiliation: Department of Experimental Immunology and Department of Clinical Immunology and Rheumatology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Iris M
authors.initials: IM
authors.lastname: Van Baarsen
authors.affiliation: Division of Cardiology, Department of Medicine, University of Colorado Denver, Aurora, Colorado, USA.
authors.forename: Bradley S
authors.initials: BS
authors.lastname: Ferguson
authors.affiliation: Department of Experimental Immunology and Department of Clinical Immunology and Rheumatology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.|Laboratory of Translational Immunology and Department of Rheumatology and Clinical Immunology, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Samuel
authors.initials: S
authors.lastname: García
authors.affiliation: Department of Experimental Immunology and Department of Clinical Immunology and Rheumatology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.|Laboratory of Translational Immunology and Department of Rheumatology and Clinical Immunology, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Beatriz
authors.initials: B
authors.lastname: Malvar Fernandez
authors.affiliation: Division of Cardiology, Department of Medicine, University of Colorado Denver, Aurora, Colorado, USA.
authors.forename: Timothy A
authors.initials: TA
authors.lastname: McKinsey
authors.affiliation: Department of Experimental Immunology and Department of Clinical Immunology and Rheumatology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.|GlaxoSmithKline, Stevenage, UK.|Cambridge University, Cambridge, UK.
authors.forename: Paul P
authors.initials: PP
authors.lastname: Tak
authors.affiliation: Italfarmaco, Cinisello Balsamo, Italy.
authors.forename: Gianluca
authors.initials: G
authors.lastname: Fossati
authors.affiliation: Italfarmaco, Cinisello Balsamo, Italy.
authors.forename: Paolo
authors.initials: P
authors.lastname: Mascagni
authors.affiliation: Department of Experimental Immunology and Department of Clinical Immunology and Rheumatology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Dominique L
authors.initials: DL
authors.lastname: Baeten
authors.affiliation: Department of Experimental Immunology and Department of Clinical Immunology and Rheumatology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.|Laboratory of Translational Immunology and Department of Rheumatology and Clinical Immunology, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Kris A
authors.initials: KA
authors.lastname: Reedquist
mesh_terms: D000107:Acetylation; D000328:Adult; D000368:Aged; D001172:Arthritis, Rheumatoid / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D002478:Cells, Cultured; D015536:Down-Regulation / Q000502:physiology; D005260:Female; D005347:Fibroblasts / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000276:immunology / Q000502:physiology; D006655:Histone Deacetylases / Q000235:genetics / Q000502:physiology*; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism*; D016899:Interferon-beta / Q000096:biosynthesis; D053583:Interleukin-1beta / Q000096:biosynthesis / Q000235:genetics; D008297:Male; D008875:Middle Aged; D010766:Phosphorylation; D050794:STAT1 Transcription Factor / Q000378:metabolism; D013583:Synovial Membrane / Q000378:metabolism; D000070918:Synoviocytes / Q000276:immunology / Q000378:metabolism*; D000099186:Histone Deacetylase 3
chemical_list: D006655:Histone Deacetylases; D018836:Inflammation Mediators; D016899:Interferon-beta; D053583:Interleukin-1beta; D050794:STAT1 Transcription Factor; D000099186:Histone Deacetylase 3; C494079:STAT1 protein, human
keywords: Cytokines; Fibroblasts; Inflammation; Rheumatoid Arthritis