Histone deacetylase 3 regulates the inflammatory gene expression programme of rheumatoid arthritis fibroblast-like synoviocytes

Ann Rheum Dis. 2017 Jan;76(1):277-285. doi: 10.1136/annrheumdis-2015-209064. Epub 2016 Jul 25.


Objectives: 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.

Keywords: Cytokines; Fibroblasts; Inflammation; Rheumatoid Arthritis.

MeSH terms

  • Acetylation
  • Adult
  • Aged
  • Arthritis, Rheumatoid / genetics
  • Arthritis, Rheumatoid / immunology
  • Arthritis, Rheumatoid / metabolism*
  • Cells, Cultured
  • Down-Regulation / physiology
  • Female
  • Fibroblasts / metabolism*
  • Gene Expression Regulation / immunology
  • Gene Expression Regulation / physiology
  • Histone Deacetylases / genetics
  • Histone Deacetylases / physiology*
  • Humans
  • Inflammation Mediators / metabolism*
  • Interferon-beta / biosynthesis
  • Interleukin-1beta / biosynthesis
  • Interleukin-1beta / genetics
  • Male
  • Middle Aged
  • Phosphorylation
  • STAT1 Transcription Factor / metabolism
  • Synovial Membrane / metabolism
  • Synoviocytes / immunology
  • Synoviocytes / metabolism*


  • Inflammation Mediators
  • Interleukin-1beta
  • STAT1 Transcription Factor
  • STAT1 protein, human
  • Interferon-beta
  • Histone Deacetylases
  • histone deacetylase 3