RT Journal Article
T1 Akt activity protects rheumatoid synovial fibroblasts from Fas-induced apoptosis by inhibition of Bid cleavage
A1 García, Samuel
A1 Lyz, Miriam
A1 Gómez-Reino Carnota, Juan Jesús
A1 Conde, Carmen
K1 Extrinsic Apoptotic Pathway
K1 Synovial Hyperplasia
K1 Fisher Bioblock Scientific
K1 Fluostar Optimum Microplate Reader
K1 Fibroblast Like Synovial
AB IntroductionSynovial hyperplasia is a main feature of rheumatoid arthritis pathology that leads to cartilage and bone damage in the inflamed joints. Impaired apoptosis of resident synoviocytes is pivotal in this process. Apoptosis resistance seems to involve defects in the extrinsic and intrinsic apoptotic pathways. The aim of this study was to investigate the association of PI3Kinase/Akt and the mitochondrial apoptotic pathway in the resistance of rheumatoid arthritis (RA) fibroblast like synovial cells (FLS) to Fas-mediated apoptosis.MethodsApoptosis was assessed by ELISA quantification of nucleosomal release, Hoechst staining and activated caspase-3/7 measure in cultured RA FLS stimulated with anti-Fas antibody. Two Phosphoinositol-3-kinase/protein Kinase B (PI3 Kinase) inhibitors, Wortmannine and LY294002, were used before anti-Fas stimulation. Proapoptotic BH3 interacting domain death agonist (Bid) was suppressed in RA FLS by small interfering RNA (siRNA) transfection. Bid was overexpressed by transfection with the pDsRed2-Bid vector. Phosphorylated Akt, caspase-9, and Bid expression were analysed by western blot.ResultsPI3 kinase inhibition sensitizes RA FLS to Fas-induced apoptosis by increasing cleavage of Bid protein. Bid suppression completely abrogated Fas-induced apoptosis and Bid overexpression highly increased apoptotic rate of RA FLS in association with cleavage of caspase-9.ConclusionsIn RA FLS, phosphorylation of Akt protects against Fas-induced apoptosis through inhibition of Bid cleavage. The connection between the extrinsic and the intrinsic apoptotic pathways are critical in this Fas- mediated apoptosis and points to PI3Kinase as potential therapeutic target for RA
PB BMC
SN 1478-6354
YR 2010
FD 2010
LK http://hdl.handle.net/10347/23076
UL http://hdl.handle.net/10347/23076
LA eng
NO García, S., Liz, M., Gómez-Reino, J.J. et al. Akt activity protects rheumatoid synovial fibroblasts from Fas-induced apoptosis by inhibition of Bid cleavage. Arthritis Res Ther 12, R33 (2010). https://doi.org/10.1186/ar2941
NO This work was supported by grant 06/0681, by RETICS Program, RD08/0075 (RIER), both from Fondo de Investigación Sanitaria, Instituto de Salud Carlos III within the VI PN de I+D+I 2008-2011 with participation of FEDER funds (European Union) and by a grant for Fundación Mutua Madrileña. S.G. is supported by Xunta de Galicia
DS Minerva
RD 24 abr 2026