Article Text

A1.20 HDAC5 regulates CXCL chemokine expression in RA FLS via the transcription factor IRF1
  1. C Angiolilli1,
  2. A M Grabiec1,
  3. B S Ferguson2,
  4. B Malvar Fernandez1,
  5. P P Tak1,3,
  6. T McKinsey2,
  7. D L Baeten1,
  8. K A Reedquist1
  1. 1Department of Experimental Immunology, Academic Medical Center, University of Amsterdam, and Amsterdam Rheumatology and Immunology Center (AMC campus), Amsterdam, The Netherlands
  2. 2University of Colorado – Denver, Denver, CO
  3. 3Currently also GlaxoSmithKline and Cambridge University, Cambridge, UK


Background and Objectives HDAC inhibitors (HDACi) display anti-inflammatory properties in animal and in vitro models of rheumatoid arthritis (RA), as well as initial safety and efficacy in the treatment of systemic onset juvenile idiopathic arthritis. However, most currently available HDACi display relatively little selectivity for class I (HDAC 1-3, 8) and class II (HDAC 4-7, 9, 10) HDACs, let alone individual HDACs. The present study aims to better characterise the different contributions of HDAC family members to the inflammatory activation of RA fibroblast-like synoviocytes (FLS).

Materials and Methods HDAC mRNA expression in RA FLS was measured by quantitative PCR, and the activity of class I, IIa and IIb HDACs was assessed by enzymatic assays. FLS were either transduced with adenoviral GFP-HDAC5 or transfected with HDAC5 siRNA, and gene expression was analysed by qPCR array, while chemokine production was measured by ELISA. Analysis of transcription factors was performed using DNA-binding and ELISA-based assays.

Results Class IIa HDAC5 mRNA expression, but not class IIa HDAC activity, was significantly and selectively reduced after RA FLS stimulation with TNFα and IL-1β. Mimicking of HDAC5 downregulation by use of siRNA, and adenoviral overexpression of HDAC5, demonstrated that of 84 inflammation-related gene products, HDAC5 downregulation was sufficient and required to allow optimal expression of IFN-B, CXCL9, CXCL10, and CXCL11. Promoter analysis of these genes compared to non-regulated genes indicated a significant enrichment in this gene set for NF-KB, STAT1 and IRF1 binding sites. Silencing of HDAC5 expression had no effect on DNA-binding activity of MEF2 transcription factors, the best described targets of class IIa HDACs, nor NF-KB or STAT1. However, HDAC5-silencing significantly enhanced IL-1β-dependent nuclear accumulation of IRF1.

Conclusions Our results show that mRNA expression and activity of distinct HDAC members in RA FLS are regulated in a different fashion by inflammatory stimuli. Silencing of class IIa HDAC5 increases CXCL chemokine production, associated with enhanced nuclear accumulation of IRF1, a transcription factor required for induction of these genes. Our results suggest that the design of HDACi targeting specific HDACs can be used to selectively modulate inflammatory gene expression in RA.

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