Activated Ras modifies the proliferative response of rheumatoid synovial cells to TNF-alpha and TGF-alpha.
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 3H-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.


CONCLUSIONS
Ras modulates the proliferative response of RSF to TNF-alpha and TGF-alpha.
Kitasato
H
H
Department of Microbiology, Kitasato University, School of Medicine, Sagamihara, Japan.
Noda
M
M
Akahoshi
T
T
Okamoto
R
R
Koshino
T
T
Murakami
Y
Y
Inoue
M
M
Kawai
S
S
D017209:Apoptosis / Q000187:drug effects; D001172:Arthritis, Rheumatoid / Q000473:pathology*; D015152:Blotting, Northern; D002455:Cell Division / Q000235:genetics; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D005419:Flavonoids / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000502:physiology; D015689:Oncogene Protein p21(ras) / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology; D013268:Stimulation, Chemical; D013583:Synovial Membrane / Q000166:cytology / Q000473:pathology*; D016211:Transforming Growth Factor alpha / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
D004791:Enzyme Inhibitors; D005419:Flavonoids; D016211:Transforming Growth Factor alpha; D014409:Tumor Necrosis Factor-alpha; D020928:Mitogen-Activated Protein Kinases; D015689:Oncogene Protein p21(ras); C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one