Arthritis and rheumatism · 2002
Cyclosporine inhibition of vascular endothelial growth factor production in rheumatoid synovial fibroblasts.
СтатьяПоддержка исследования: вне правительства СШАНазвание и аннотация: Перевод в очереди
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Cho Mi-La, Cho Chul-Soo, Min So-Youn, Kim Seung-Hoon, Lee Shin-Seok, Kim Wan-Uk, Min Do-June, Min Jun-Ki, Youn Jeehee, Hwang Sue-Yun, Park Sung-Hwan, Kim Ho-Youn
Аннотация
OBJECTIVE: To determine the antiangiogenic effect of cyclosporin A (CSA) in rheumatoid arthritis (RA).
METHODS: We investigated the effect of CSA on the production of vascular endothelial growth factor (VEGF) by rheumatoid synovial fibroblasts. Fibroblast-like synoviocytes (FLS) were prepared from the synovial tissues of RA patients, and cultured in the presence of CSA. The production of VEGF by FLS was measured in culture supernatants by enzyme-linked immunosorbent assay. The VEGF messenger RNA (mRNA) expression and activator protein 1 (AP-1) binding activity for VEGF transcription were determined by polymerase chain reaction and electrophoretic mobility shift assay, respectively.
RESULTS: CSA dose-dependently inhibited both constitutive and transforming growth factor beta-induced VEGF production at the protein and mRNA levels. The suppressive action of CSA on VEGF synthesis was calcineurin dependent, as evidenced by a comparable inhibition by FK-506. Agonists of cAMP, 3-isobutyl-1-methylxanthine and N-2-O-dibutyryl-cAMP, mimicked the effect of CSA on VEGF production, while a cAMP antagonist, 2',3'-dideoxyadenosine, abrogated the effect of CSA. A gel mobility shift assay showed that the inhibitory effect of CSA was associated with decreased AP-1 binding activity to the VEGF promoter, in a cAMP-dependent manner.
CONCLUSION: CSA may exert an antiangiogenic effect by inhibiting AP-1-mediated VEGF expression in rheumatoid synovial fibroblasts.
METHODS: We investigated the effect of CSA on the production of vascular endothelial growth factor (VEGF) by rheumatoid synovial fibroblasts. Fibroblast-like synoviocytes (FLS) were prepared from the synovial tissues of RA patients, and cultured in the presence of CSA. The production of VEGF by FLS was measured in culture supernatants by enzyme-linked immunosorbent assay. The VEGF messenger RNA (mRNA) expression and activator protein 1 (AP-1) binding activity for VEGF transcription were determined by polymerase chain reaction and electrophoretic mobility shift assay, respectively.
RESULTS: CSA dose-dependently inhibited both constitutive and transforming growth factor beta-induced VEGF production at the protein and mRNA levels. The suppressive action of CSA on VEGF synthesis was calcineurin dependent, as evidenced by a comparable inhibition by FK-506. Agonists of cAMP, 3-isobutyl-1-methylxanthine and N-2-O-dibutyryl-cAMP, mimicked the effect of CSA on VEGF production, while a cAMP antagonist, 2',3'-dideoxyadenosine, abrogated the effect of CSA. A gel mobility shift assay showed that the inhibitory effect of CSA was associated with decreased AP-1 binding activity to the VEGF promoter, in a cAMP-dependent manner.
CONCLUSION: CSA may exert an antiangiogenic effect by inhibiting AP-1-mediated VEGF expression in rheumatoid synovial fibroblasts.
Предметные рубрики MeSH
Antirheumatic AgentsCells, CulturedCyclic AMPCyclosporineDown-RegulationEndothelial Growth FactorsFibroblastsGene ExpressionHumansImmunosuppressive AgentsLymphokinesProtein BindingRNA, MessengerSynovial MembraneTacrolimusTranscription Factor AP-1Vascular Endothelial Growth Factor AVascular Endothelial Growth Factors