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Rheumatology Advance Access published online on February 19, 2009
Rheumatology, doi:10.1093/rheumatology/ken502
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© The Author 2009. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Poly(ADP-ribose) polymerase suppression protects rheumatoid synovial fibroblasts from Fas-induced apoptosis

Samuel García1, Antonio Mera1, Juan J. Gómez-Reino1,2 and Carmen Conde1

1Research Laboratory and Rheumatology Unit, Hospital Clínico Universitario de Santiago de Compostela and 2Department of Medicine, University of Santiago de Compostela, Santiago de Compostela, Spain.

Correspondence to: Carmen Conde, Laboratorio de Investigación 5, Hospital Clínico Universitario de Santiago, 15706- Santiago de Compostela, Spain. E-mail: Carmen.Conde.Muro{at}sergas.es


  Abstract

Objectives. To investigate the effect of poly(ADP-ribose) polymerase 1 (PARP-1) suppression on CD95/Apo-1 (Fas)-induced apoptosis in fibroblast-like synoviocytes (FLS) from RA patients.

Methods. Apoptosis, determined by Hoechst staining and quantification of nucleosomal release by ELISA, was induced by stimulation with anti-Fas antibody with or without pre-treatment with cycloheximide (CHX). PARP-1 and poly(ADP-ribose) glycohydrolase (PARG) were suppressed in RA FLS by small interfering RNA (siRNA) transfection. Fas-associated via death domain (FADD), pro-caspase-8, Fas, c-Fas-associated death domain-like IL-1b-converting enzyme-inhibitory protein (FLIP) expression, and AKT and GSK phosphorylation were analysed by western blot.

Results. PARP-1-deficient FLS showed significantly lower apoptosis than non-transfected and control siRNA-transfected FLS. The expression of death-inducing signaling complex (DISC) components such as Fas, FADD and pro-caspase-8 was not modified by PARP-1 suppression; however, FLS lacking PARP-1 showed high activation of the Akt-GSK survival pathway and up-regulation of the c-FLIP-S isoform after Fas triggering. Inhibition of PI3K/Akt pathway did not modify the difference between PARP-1-competent or -deficient FLS in Fas-mediated apoptosis or c-FLIP-S expression. Poly(ADP-ribose) accumulation induced by PARG supression did not modify the apoptotic response.

Conclusion. PARP-1 deficiency increases the resistance of RA FLS to Fas-induced apoptosis through activation of the Akt-GSK survival pathway and up-regulation of c-FLIP-S isoform.

KEY WORDS: Rheumatoid arthritis, Poly(ADP-ribose) polymerase1, Apoptosis, Fas-associated death domain-like IL-1b-converting enzyme-inhibitory protein, Phosphoinositol-3-kinase/protein kinase B

Submitted 24 September 2008; revised version accepted 10 December 2008.
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