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.
- rheumatoid arthritis