Article Text
Abstract
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)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 patients with RA. PARP inhibitors also decreased TNF-induced RA FLS proliferation. PARP inhibition reduced TNF-induced JNK phosphorylation 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.
Statistics from Altmetric.com
Footnotes
Funding: This work was supported by Fondo de Investigación Sanitaria, Instituto de Salud Carlos III (Spain), grants 02/0490, G03/152 and 05/0477 with participation of FEDER funds (European Union), and by grants from the DXID (Xunta de Galicia). SG and AB are supported by Xunta de Galicia.
Competing interests: None declared.