Selective Susceptibility of Synovial Fibroblasts Isolated from Patients with Rheumatoid Arthritis to TRAIL -induced Cell Death

Cho, Won Gil; Leem, Hyun Sung; Paik, Doo Jin; Chung, Ho Sam; Kim, Won Kyu; Choi, Chung Hyuk; Youn, Jeehee

Abstract

TNF -related apoptosis inducing ligand (TRAIL) is a member of TNF ligand superfamily. TRAIL transduces death signal through two distinct receptors, TRAILR -1I and TRAILR -2, while the engagement of TRAILR -3 and TRAILR -4 interferes with TRAIL -induced apoptosis. The profile of TRAILR expression has been reported to be a mechanism by which transformed cells undergo apoptosis in response to TRAIL while normal cells do not. Rheumatoid arthritis (RA) is an inflammatory autoimmune disease which is characterized by the hyperplasia of synovial membrane. The dysregulation of apoptosis in synoviocytes has been suggested to contribute to synovial hyperplasia. Synovial fibroblasts obtained from patients with RA have been reported to exhibit several semi - transformed aspects. To investigate whether RA synovial fibroblasts acquire the susceptibility to TRAIL -induced apoptosis, synovial fibroblast lines obtained from 2 RA patients and two osteoarthritis (OA) patients were cultured in the presence of recombinant human TRAIL and followed by MTT assay. TRAIL treatment resulted in a significant decrease in the viability of both lines of RA cells, indicating TRAIL -induced cell death of RA synovial fibroblasts, whereas OA synovial fibroblasts and normal human dermal fibroblasts were either resistant or less sensitive to TRAIL as compared with RA synovial fibroblasts. In RT -PCR analyses, the expression levels of TRAILR 4 in RA synovial fibroblasts were lower than in OA synovial fibroblasts, while other receptors in both cell lines were expressed at comparable levels. Immunohistochemical studies showed that in RA synovial tissues TRAILR -3cells were mainly leukocyte infiltrates, implying that such leukocyte infiltrates play a role in the perpetuation of the disease. Taken together, these results suggest that RA synovial fibroblasts acquire the susceptibility to TRAIL -induced cell death during disease progression and this death signal may be regulated by, at least in part, differential expression of TRAILR -4 molecule.