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Poly(ADP-ribose) polymerase inhibition reduces tumor necrosis factor-induced inflammatory response in rheumatoid synovial fibroblasts

S García¹, A Bodaño¹, J L Pablos², J J Gómez-Reino¹, C Conde¹

¹ Research Laboratory and Rheumatology Unit, Hospital Clínico Universitario de Santiago de Compostela, Spain
² Rheumatology Unit, Hospital 12 de Octubre, Madrid, Spain

C Conde, Laboratorio de Investigación 5, Hospital Clínico Universitario de Santiago. 15706- Santiago de Compostela. Spain; Carmen.Conde.Muro{at}sergas.es

Objectives: 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)B 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 NFB 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.

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• Garcia, S., Mera, A., Gomez-Reino, J. J., Conde, C. (2009). Poly(ADP-ribose) polymerase suppression protects rheumatoid synovial fibroblasts from Fas-induced apoptosis. Rheumatology (Oxford) 48: 483-489 [Abstract] [Full Text]