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


METHODS
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.


RESULTS
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, suggesting that Rho was responsible for the antiapoptotic effects of tryptase.


CONCLUSIONS
These results demonstrate that tryptase has a strong antiapoptotic effect on RASFs through the activation of Rho. Thus, we propose that the release of tryptase by mast cells leads to the binding of tryptase to PAR-2 on RASFs and inhibits the apoptosis of RASFs via the activation of Rho. Such mechanisms could play a pivotal role in the marked proliferation of RASFs and hyperplasia of synovial tissue seen in RA synovium.
University of Occupational and Environmental Health, Kitakyushu, Japan, and University of Pennsylvania, Philadelphia, Pennsylvania, USA.
Norifumi
N
Sawamukai
Sonosuke
S
Yukawa
Kazuyoshi
K
Saito
Shingo
S
Nakayamada
Taku
T
Kambayashi
Yoshiya
Y
Tanaka
D017209:Apoptosis / Q000187:drug effects*; D001172:Arthritis, Rheumatoid / Q000201:enzymology / Q000503:physiopathology*; D002478:Cells, Cultured; D005347:Fibroblasts / Q000201:enzymology / Q000276:immunology / Q000473:pathology*; D005434:Flow Cytometry; D006801:Humans; D007150:Immunohistochemistry; D008407:Mast Cells / Q000201:enzymology; D008875:Middle Aged; D044464:Receptor, PAR-2 / Q000235:genetics / Q000378:metabolism; D012234:Rho Factor / Q000276:immunology*; D015398:Signal Transduction / Q000276:immunology; D013583:Synovial Membrane / Q000201:enzymology / Q000473:pathology*; D053802:Tryptases / Q000276:immunology / Q000378:metabolism / Q000494:pharmacology*
D044464:Receptor, PAR-2; D012234:Rho Factor; D053802:Tryptases