Mast cell-derived tryptase inhibits apoptosis of human rheumatoid synovial fibroblasts via rho-mediated signaling

Arthritis and Rheumatism
Norifumi SawamukaiYoshiya Tanaka

Abstract

An abundance of mast cells are found in the synovium of patients with rheumatoid arthritis (RA). However, the role of mast cells in the pathogenesis of RA remains unclear. This study was undertaken to elucidate a role for mast cells in RA by investigating the antiapoptotic effects of tryptase, a major product of mast cells, on RA synovial fibroblasts (RASFs). RA synovial tissue was obtained from RA patients during joint replacement surgery, and histologic changes in the tissue were examined. The expression of cell surface molecules and apoptotic markers on RASFs were detected by flow cytometry. Rho activation was determined using a pull-down assay. Mast cells, bearing both c-Kit and tryptase, accumulated in the sublining area of proliferating synovial tissue from RA patients. Protease-activated receptor 2 (PAR-2), a receptor for tryptase, was expressed on RASFs in the lining area, close to tryptase-positive mast cells in the RA synovium. Fas-mediated apoptosis of RASFs was significantly inhibited, in a dose-dependent manner, by the addition of tryptase, and this effect correlated with increased activation of Rho kinase. Furthermore, Y27632, a Rho kinase inhibitor, reduced the antiapoptotic effect of tryptase on RASFs, suggestin...Continue Reading

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Apoptosis

Apoptosis is a specific process that leads to programmed cell death through the activation of an evolutionary conserved intracellular pathway leading to pathognomic cellular changes distinct from cellular necrosis