Fas activation of a proinflammatory program in rheumatoid synoviocytes and its regulation by FLIP and caspase 8 signaling
Abstract
The 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. Cultured 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-kappaB 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, IkappaB alpha, 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. Fas stimulation activated NF-kappaB and AP-1, and this response required caspase activity, since Z-VAD-FMK in...Continue Reading
References
NF-kappaB inducers upregulate cFLIP, a cycloheximide-sensitive inhibitor of death receptor signaling
Citations
Fractalkine mediates T cell-dependent proliferation of synovial fibroblasts in rheumatoid arthritis.
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