title: Inflammatory cytokines epigenetically regulate rheumatoid arthritis fibroblast-like synoviocyte activation by suppressing HDAC5 expression.
abstract: OBJECTIVE
  Epigenetic modifications play an important role in the regulation of gene transcription and cellular function. Here, we examined if pro-inflammatory factors present in the inflamed joint of patients with rheumatoid arthritis (RA) could regulate histone deacetylase (HDAC) expression and function in fibroblast-like synoviocytes (FLS).
  
  
  METHODS
  Protein acetylation in synovial tissue was assessed by immunohistochemistry. The mRNA levels of HDAC family members and inflammatory mediators in the synovial tissue and the changes in HDAC expression in RA FLS were measured by quantitative (q) PCR. FLS were either transfected with HDAC5 siRNA or transduced with adenoviral vector encoding wild-type HDAC5 and the effects of HDAC5 manipulation were examined by qPCR arrays, ELISA and ELISA-based assays.
  
  
  RESULTS
  Synovial class I HDAC expression was associated with local expression of tumour necrosis factor (TNF) and matrix metalloproteinase-1, while class IIa HDAC5 expression was inversely associated with parameters of disease activity (erythrocyte sedimentation rate, C-reactive protein, Disease Activity Score in 28 Joints). Interleukin (IL)-1β or TNF stimulation selectively suppressed HDAC5 expression in RA FLS, which was sufficient and required for optimal IFNB, CXCL9, CXCL10 and CXCL11 induction by IL-1β, associated with increased nuclear accumulation of the transcription factor, interferon regulatory factor 1(IRF1).
  
  
  CONCLUSIONS
  Inflammatory cytokines suppress RA FLS HDAC5 expression, promoting nuclear localisation of IRF1 and transcription of a subset of type I interferon response genes. Our results identify HDAC5 as a novel inflammatory mediator in RA, and suggest that strategies rescuing HDAC5 expression in vivo, or the development of HDAC inhibitors not affecting HDAC5 activity, may have therapeutic applications in RA treatment.
authors.affiliation: Department of Experimental Immunology and Department of Clinical Immunology and Rheumatology, Academic Medical Center, University of Amsterdam, Amsterdam, 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.
authors.forename: Aleksander M
authors.initials: AM
authors.lastname: Grabiec
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: Center of Experimental Rheumatology, University Hospital Zurich, Zurich, Switzerland.
authors.forename: Caroline
authors.initials: C
authors.lastname: Ospelt
authors.affiliation: Department of Experimental Immunology and Department of Clinical Immunology and Rheumatology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Beatriz
authors.initials: B
authors.lastname: Malvar Fernandez
authors.affiliation: Department of Experimental Immunology and Department of Clinical Immunology and Rheumatology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Inge E
authors.initials: IE
authors.lastname: van Es
authors.affiliation: Department of Experimental Immunology and Department of Clinical Immunology and Rheumatology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Lisa G M
authors.initials: LG
authors.lastname: van Baarsen
authors.affiliation: Center of Experimental Rheumatology, University Hospital Zurich, Zurich, Switzerland.
authors.forename: Steffen
authors.initials: S
authors.lastname: Gay
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: 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.
authors.forename: Kris A
authors.initials: KA
authors.lastname: Reedquist
mesh_terms: D000328:Adult; D000368:Aged; D001172:Arthritis, Rheumatoid / Q000235:genetics / Q000378:metabolism*; D001799:Blood Sedimentation; D002097:C-Reactive Protein / Q000032:analysis; D016207:Cytokines / Q000235:genetics*; D044127:Epigenesis, Genetic; D005260:Female; D005347:Fibroblasts / Q000378:metabolism*; D006655:Histone Deacetylases / Q000378:metabolism*; D006801:Humans; D050856:Interferon Regulatory Factor-1 / Q000235:genetics; D053583:Interleukin-1beta / Q000378:metabolism; D008297:Male; D020781:Matrix Metalloproteinase 1 / Q000378:metabolism; D008875:Middle Aged; D012333:RNA, Messenger / Q000378:metabolism; D012720:Severity of Illness Index; D013583:Synovial Membrane / Q000166:cytology*; D014158:Transcription, Genetic; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D016207:Cytokines; D050856:Interferon Regulatory Factor-1; D053583:Interleukin-1beta; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D002097:C-Reactive Protein; C522360:MMP1 protein, human; D020781:Matrix Metalloproteinase 1; C404500:HDAC5 protein, human; D006655:Histone Deacetylases
keywords: Chemokines; Fibroblasts; Inflammation; Rheumatoid Arthritis