3-4-dihydro-5-(4-(1-piperidinyl)butoxy)-1(2h)-isoquinolinone and Arthritis--Rheumatoid

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).. 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)kappaB binding by electrophoretic mobility shift assay.. 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 kappaB binding activities were partially impaired by treatment with PARP inhibitors or by PARP-1 knockdown.. 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.

Topics: 1-Naphthylamine; Apoptosis; Arthritis, Rheumatoid; Blotting, Western; Cell Proliferation; Cells, Cultured; Depression, Chemical; Electrophoretic Mobility Shift Assay; Fibroblasts; Humans; Interleukin-6; Interleukin-8; Isoquinolines; Mitogen-Activated Protein Kinases; Naphthalimides; NF-kappa B; Piperidines; Poly(ADP-ribose) Polymerase Inhibitors; Poly(ADP-ribose) Polymerases; Quinolones; Reverse Transcriptase Polymerase Chain Reaction; RNA Interference; RNA, Small Interfering; Synovial Membrane; Transcription Factor AP-1; Tumor Necrosis Factors