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

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)kappa 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 NF kappa B 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.