title: Poly(ADP-ribose) polymerase inhibition reduces tumor necrosis factor-induced inflammatory response in rheumatoid synovial fibroblasts.
abstract: OBJECTIVE
  To investigate the effect of poly(ADP-ribose) polymerase (PARP) inhibition on the production of inflammatory mediators and proliferation in tumour necrosis factor (TNF)-stimulated fibroblast-like synoviocytes (FLS) from patients with rheumatoid arthritis (RA).
  
  
  METHODS
  Cultured FLS from patients with RA were treated with two PARP inhibitors, 3,4-dihydro-5-[4-1(1-piperidinyl)buthoxy]-1(2H)-isoquinolinona (DPQ) or 4-amino-1,8-naphthalimida (ANI) before TNF stimulation. PARP-1 expression was also suppressed in RA FLS by small interfering RNA (siRNA) transfection. Expression and secretion of inflammatory mediators were analysed by quantitative polymerase chain reaction and by enzyme-linked immunosorbent assay, respectively. Proliferation of RA FLS was also determined. Mitogen-activated protein kinase (MAPK) activity was analysed by western blot assay and activator protein (AP)-1 and nuclear factor (NF)kappaB binding by electrophoretic mobility shift assay.
  
  
  RESULTS
  We show, for the first time, that PARP inhibition either with specific inhibitors or by siRNA transfection significantly reduced TNF-induced cytokine and chemokine expression in FLS from patients with RA. PARP inhibitors also decreased TNF-induced RA FLS proliferation. PARP inhibition reduced TNF-induced JNK phosphorylation and AP-1 and NF kappaB binding activities were partially impaired by treatment with PARP inhibitors or by PARP-1 knockdown.
  
  
  CONCLUSIONS
  PARP inhibition reduces the production of inflammatory mediators and the proliferation of RA FLS (in response to TNF), suggesting that PARP inhibitors could have therapeutic benefits in RA.
authors: Research Laboratory and Rheumatology Unit, Hospital Clínico Universitario de Santiago de Compostela, Spain.
authors: S
authors: S
authors: García
authors: A
authors: A
authors: Bodaño
authors: J L
authors: JL
authors: Pablos
authors: J J
authors: JJ
authors: Gómez-Reino
authors: C
authors: C
authors: Conde
mesh_terms: D015057:1-Naphthylamine / Q000031:analogs & derivatives* / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D001172:Arthritis, Rheumatoid / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D015153:Blotting, Western; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D003864:Depression, Chemical; D024202:Electrophoretic Mobility Shift Assay; D005347:Fibroblasts / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D015850:Interleukin-6 / Q000276:immunology; D016209:Interleukin-8 / Q000276:immunology; D007546:Isoquinolines / Q000494:pharmacology*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D053644:Naphthalimides / Q000494:pharmacology*; D010880:Piperidines / Q000494:pharmacology*; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011065:Poly(ADP-ribose) Polymerases / Q000235:genetics; D015363:Quinolones / Q000494:pharmacology*; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000494:pharmacology; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D013583:Synovial Membrane / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D018808:Transcription Factor AP-1 / Q000378:metabolism; D048069:Tumor Necrosis Factors / Q000494:pharmacology*
chemical_list: D015850:Interleukin-6; D016209:Interleukin-8; D007546:Isoquinolines; D016328:NF-kappa B; D053644:Naphthalimides; D010880:Piperidines; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D015363:Quinolones; D034741:RNA, Small Interfering; D018808:Transcription Factor AP-1; D048069:Tumor Necrosis Factors; C086538:4-amino-1,8-naphthalimide; C108729:3,4-dihydro-5-(4-(1-piperidinyl)butoxy)-1(2H)-isoquinolinone; D015057:1-Naphthylamine; D011065:Poly(ADP-ribose) Polymerases; D020928:Mitogen-Activated Protein Kinases