Activated Ras modifies the proliferative response of rheumatoid synovial cells to TNF-α and TGF-α

Objective: To study the role of the Ras/mitogen-activated protein kinase (MAPK) pathway in the proliferative response of rheumatoid synovial fibroblast (RSF) to tumor necrosis factor (TNF)-alpha and transforming growth factor (TGF)-alpha. Methods: V-Ki-ras gene was introduced into RSF using a retrovirus and the proliferative response of these cells to TNF-alpha or TGF-alpha was estimated by measuring the uptake of H-3-thymidine. The effect of a mitogen-activated protein kinase kinase (MEK) inhibitor, PD98059, was also investigated. Results: Consistent with previous reports, TNF-alpha and TGF-alpha stimulated the proliferation of RSF. When the v-Ki-ras gene was expressed, the basal growth rate of these cells was increased, but their growth was suppressed by TNF-alpha or TGF-alpha. The latter effect was abolished when the cells were exposed to a relatively low concentration of PD98059. Conclusion: Ras modulates the proliferative response of RSF to TNF-alpha and TGF-alpha.