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Poly(ADP-ribose) polymerase inhibition reduces TNF-induced inflammatory response in rheumatoid synovial fibroblasts.
  1. Samuel García (samugp13{at}yahoo.es)
  1. Hospital Clinico Universitario de Santiago de Compostela, Spain
    1. Ana Bodaño (anabodano{at}hotmail.es)
    1. Hospital Clinico Universitario de Santiago de Compostela, Spain
      1. Jose Luis Pablos (jlpablos{at}h12o.es)
      1. Hospital 12 de Octubre, Spain
        1. Juan J Gómez-Reino (juan.gomez-reino.carnota{at}sergas.es)
        1. Hospital Clinico Universitario de Santiago, Spain
          1. Carmen Conde (carmen.conde.muro{at}sergas.es)
          1. Hospital Clinico Universitario de Santiago, Spain

            Abstract

            Objectives: To investigate the effect of poly (ADP-ribose) polymerase (PARP) inhibition on the production of inflammatory mediators and proliferation in TNF-stimulated fibroblast like synoviocytes cells (FLS) from RA patients.

            Methods: Cultured FLS from RA patients 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. MAPK activity was analysed by western blot assay and AP-1 and NF-κB 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 RA patients. PARP inhibitors also decreased TNF-induced RA FLS proliferation. PARP inhibition reduced TNF-induced JNK phosphorilation and AP-1 and NFκB binding activities were partially impaired by treatment with PARP inhibitors or by PARP-1 knockdown.

            Conclusion: 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.

            • chemokines
            • cytokines
            • inflammation
            • rheumatoid arthritis

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