Cyclosporine inhibition of vascular endothelial growth factor production in rheumatoid synovial fibroblasts

Mi La Cho, Chul Soo Cho, So Youn Min, Seung Hoon Kim, Shin Seok Lee, Wan Uk Kim, Do June Min, Jun Ki Min, Jeehee Youn, Sue Yun Hwang, Sung Hwan Park, Ho Youn Kim

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64 Scopus citations

Abstract

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 β-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-2-0-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.

Original languageEnglish (US)
Pages (from-to)1202-1209
Number of pages8
JournalArthritis and rheumatism
Volume46
Issue number5
DOIs
StatePublished - May 28 2002

ASJC Scopus subject areas

  • Immunology and Allergy
  • Rheumatology
  • Immunology
  • Pharmacology (medical)

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    Cho, M. L., Cho, C. S., Min, S. Y., Kim, S. H., Lee, S. S., Kim, W. U., Min, D. J., Min, J. K., Youn, J., Hwang, S. Y., Park, S. H., & Kim, H. Y. (2002). Cyclosporine inhibition of vascular endothelial growth factor production in rheumatoid synovial fibroblasts. Arthritis and rheumatism, 46(5), 1202-1209. https://doi.org/10.1002/art.10215