RT Journal Article
T1 Fas activation of a proinflammatory program in rheumatoid synoviocytes and its regulation by FLIP and caspase 8 signaling
A1 Palao, Guillermo
A1 Galindo Izquierdo, María
A1 Ramírez Fernández, Juan Carlos
A1 Pablos Álvarez, José Luis
AB ObjectiveThe expansion of an aggressive population of fibroblast‐like synoviocytes (FLS) in rheumatoid arthritis (RA) synovium occurs despite their expression of functional death receptors and exposure to death receptor ligands. FLS can survive Fas challenge because of the constitutive expression of FLIP apoptosis inhibitor. We investigated whether Fas signaling plays a pathogenetic role by activating a nonapoptotic proinflammatory program in RA FLS.MethodsCultured RA FLS were stimulated with an agonistic anti‐Fas antibody in the presence or absence of the caspase inhibitor Z‐VAD‐FMK or after RNA interference with a short hairpin RNA expression plasmid directed against FLIP. NF‐κB and activator protein 1 (AP‐1) activation was studied by electrophoretic mobility shift assays and p65 immunofluorescence analysis, and expression of messenger RNA (mRNA) for monocyte chemoattractant protein 1, interleukin‐8, IκBα, and matrix metalloproteinases (MMPs) 1, 9, and 13 was examined by reverse transcription–polymerase chain reaction. Chemotactic activity of Fas‐activated FLS–conditioned media was studied in Transwell migration assays.ResultsFas stimulation activated NF‐κB and AP‐1, and this response required caspase activity, since Z‐VAD‐FMK inhibitor precluded it. FLIP was processed to p43 protein after Fas stimulation in a caspase‐dependent manner, and inhibition of FLIP expression resulted in reduced Fas‐triggered NF‐κB activation. Fas stimulation increased expression of mRNA for IκBα, MMPs, and chemokines, and Fas‐activated RA FLS displayed increased chemotactic activity for monocytic cells.ConclusionFas triggering may contribute to the proinflammatory features of RA FLS by activating NF‐κB and AP‐1 and by expression of relevant target genes, such as MMPs and chemokines. Fas proinflammatory signaling is dependent upon caspase activity and FLIP expression. These data implicate FLIP as a potentially important molecular switch that turns the Fas signaling away from apoptosis and toward induction of a proinflammatory phenotype in RA FLS.
PB Wiley
SN 0004-3591
SN 1529-0131
YR 2006
FD 2006
LK https://hdl.handle.net/20.500.14352/114100
UL https://hdl.handle.net/20.500.14352/114100
LA eng
NO Palao G, Santiago B, Galindo MA, Rullas JN, Alcamí J, Ramirez JC, Pablos JL. Fas activation of a proinflammatory program in rheumatoid synoviocytes and its regulation by FLIP and caspase 8 signaling. Arthritis Rheum. 2006 May;54(5):1473-81
NO Fondo de Investigación Sanitaria, Spain(grants 02/0057 and G03/152
NO Dr. Palao’s work was supported by the Fondo de Investigación Sanitaria post-FSE program
DS Docta Complutense
RD 18 abr 2025