title: Imbalance between HAT and HDAC activities in the PBMCs of patients with ankylosing spondylitis or rheumatoid arthritis and influence of HDAC inhibitors on TNF alpha production.
abstract: OBJECTIVE
  Acetylation or deacetylation of histone proteins may modulate cytokine gene transcription such as TNF alpha (TNF). We evaluated the balance between histone deacetytlase (HDAC) and histone acetyltransferase (HAT) in patients with rheumatoid arthritis (RA) or ankylosing spondylitis (AS) compared to healthy controls (HC) and determined the influence of HDAC inhibitors (trichostatin A -TSA- or Sirtinol -Sirt-) on these enzymatic activities and on the PBMC production of TNF.
  
  
  METHODS
  52 patients with RA, 21 with AS and 38 HC were evaluated. HAT and HDAC activities were measured on nuclear extracts from PBMC using colorimetric assays. Enzymatic activities were determined prior to and after ex vivo treatment of PBMC by TSA or Sirt. TNF levels were evaluated in PBMC culture supernatants in the absence or presence of TSA or Sirt.
  
  
  RESULTS
  HAT and HDAC activities were significantly reduced in AS, while these activities reached similar levels in RA and HC. Ex vivo treatment of PBMC by HDACi tended to decrease HDAC expression in HC, but Sirt significantly reduced HAT in RA. TNF production by PBMC was significantly down-regulated by Sirt in HC and AS patients.
  
  
  CONCLUSIONS
  HAT and HDAC were disturbed in AS while no major changes were found in RA. HDACi may modulate HDAC and HAT PBMC expression, especially Sirt in RA. Sirtinol was able to down regulate TNF production by PBMC in HC and AS. An imbalance between HAT and HDAC activities might provide the rationale for the development of HDACi in the therapeutic approach to inflammatory rheumatic diseases.
authors.affiliation: Clinical Investigation Center Biotherapy CBT-506, University Hospital of Besançon, Besançon, France.
authors.forename: Eric
authors.initials: E
authors.lastname: Toussirot
authors.forename: Wasim
authors.initials: W
authors.lastname: Abbas
authors.forename: Kashif Aziz
authors.initials: KA
authors.lastname: Khan
authors.forename: Marion
authors.initials: M
authors.lastname: Tissot
authors.forename: Alicia
authors.initials: A
authors.lastname: Jeudy
authors.forename: Lucile
authors.initials: L
authors.lastname: Baud
authors.forename: Ewa
authors.initials: E
authors.lastname: Bertolini
authors.forename: Daniel
authors.initials: D
authors.lastname: Wendling
authors.forename: Georges
authors.initials: G
authors.lastname: Herbein
mesh_terms: D000328:Adult; D017209:Apoptosis / Q000187:drug effects; D001172:Arthritis, Rheumatoid / Q000378:metabolism*; D016022:Case-Control Studies; D002470:Cell Survival / Q000187:drug effects; D004789:Enzyme Activation; D005260:Female; D051548:Histone Acetyltransferases / Q000378:metabolism*; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006655:Histone Deacetylases / Q000378:metabolism*; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000187:drug effects* / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D013167:Spondylitis, Ankylosing / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis*
chemical_list: D056572:Histone Deacetylase Inhibitors; D014409:Tumor Necrosis Factor-alpha; D051548:Histone Acetyltransferases; D006655:Histone Deacetylases
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