The effects of the immunosuppressant rapamycin on the growth of rheumatoid arthritis (RA) synovial fibroblast.
RA is a chronic inflammatory disease characterized by mononuclear cell infiltration and the overgrowth of synovial fibroblast. This invasive growth of synovial tissues corresponds with the progressive destruction of articular cartilage and bone. Several immunosuppressive agents, such as cyclophosphamide, cyclosporin A and mizoribine, have been clinically used to control disease progression, though relatively little is known of their effects on rheumatoid synovium. Rapamycin exhibits a strong immunosuppressive activity by acting on T cell signalling pathways. In the present study we examined the effects of rapamycin on the growth of synovial fibroblast isolated from RA patients. Platelet-derived growth factor (PDGF) is a potent growth factor in synovial fibroblasts isolated from RA patients. PDGF and serum stimulation resulted in a rapid phosphorylation of tyrosine and activation of mitogen-activated protein kinase (MAP kinase), 70-kD-S6 kinase (P70S6k) and 90-kD-S6 kinase (P90rsk). Rapamycin, a macrolide immunosuppressant, inhibited completely growth factor-induced synovial fibroblast proliferation and P70S6k activation. In contrast, tyrosine phosphorylation and activation of MAP kinases and P90rsk were not influenced by rapamycin treatment. Our data demonstrate that growth factor-mediated P70S6k activation is closely related to the growth of synovial fibroblast, and suggest the efficacy of rapamycin for controlling synovial hyperplasia in RA.
Migita
K
K
First Department of Internal Medicine, Nagasaki University School of Medicine, Japan.
Eguchi
K
K
aoyagi
T
T
Tsukada
T
T
Tsuboi
M
M
Kawabe
Y
Y
Nagataki
S
S
D001172:Arthritis, Rheumatoid / Q000276:immunology* / Q000473:pathology; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D004789:Enzyme Activation; D005347:Fibroblasts / Q000166:cytology; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D019000:Phosphotyrosine / Q000378:metabolism; D010982:Platelet-Derived Growth Factor / Q000494:pharmacology; D011090:Polyenes / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D017479:Receptors, Platelet-Derived Growth Factor / Q000502:physiology; D019893:Ribosomal Protein S6 Kinases; D015398:Signal Transduction; D020123:Sirolimus; D013583:Synovial Membrane / Q000166:cytology*
D007166:Immunosuppressive Agents; D010982:Platelet-Derived Growth Factor; D011090:Polyenes; D019000:Phosphotyrosine; D017479:Receptors, Platelet-Derived Growth Factor; D017346:Protein Serine-Threonine Kinases; D019893:Ribosomal Protein S6 Kinases; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D020123:Sirolimus