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Inflammatory cytokines epigenetically regulate rheumatoid arthritis fibroblast-like synoviocyte activation by suppressing HDAC5 expression
  1. Chiara Angiolilli1,
  2. Aleksander M Grabiec1,
  3. Bradley S Ferguson2,
  4. Caroline Ospelt3,
  5. Beatriz Malvar Fernandez1,
  6. Inge E van Es1,
  7. Lisa G M van Baarsen1,
  8. Steffen Gay3,
  9. Timothy A McKinsey2,
  10. Paul P Tak1,4,5,
  11. Dominique L Baeten1,
  12. Kris A Reedquist1
  1. 1Department of Experimental Immunology and Department of Clinical Immunology and Rheumatology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
  2. 2Division of Cardiology, Department of Medicine, University of Colorado Denver, Aurora, Colorado, USA
  3. 3Center of Experimental Rheumatology, University Hospital Zurich, Zurich, Switzerland
  4. 4GlaxoSmithKline, Stevenage, UK
  5. 5Cambridge University, Cambridge, UK
  1. Correspondence to Dr Kris A Reedquist, Department of Experimental Immunology, Academic Medical Center, University of Amsterdam, and Amsterdam Rheumatology and Immunology Center (AMC campus), Room K0-140, Meibergdreef 9, Amsterdam 1105 AZ, The Netherlands; k.a.reedquist{at}amc.uva.nl

Abstract

Objectives 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.

  • Inflammation
  • Rheumatoid Arthritis
  • Fibroblasts
  • Chemokines

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