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

Research output: Contribution to journalArticle

63 Citations (Scopus)

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 - 2002

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Vascular Endothelial Growth Factor A
Cyclosporine
Fibroblasts
Transcription Factor AP-1
Electrophoretic Mobility Shift Assay
Protein Binding
Rheumatoid Arthritis
Dideoxyadenosine
1-Methyl-3-isobutylxanthine
Messenger RNA
Calcineurin
Transforming Growth Factors
Tacrolimus
Gels
Enzyme-Linked Immunosorbent Assay
Polymerase Chain Reaction

ASJC Scopus subject areas

  • Immunology
  • Rheumatology

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

In: Arthritis and Rheumatism, Vol. 46, No. 5, 2002, p. 1202-1209.

Research output: Contribution to journalArticle

Cho, ML, Cho, CS, Min, SY, Kim, SH, Lee, SS, Kim, WU, Min, DJ, Min, JK, Youn, J, Hwang, SY, Park, SH & Kim, HY 2002, 'Cyclosporine inhibition of vascular endothelial growth factor production in rheumatoid synovial fibroblasts', Arthritis and Rheumatism, vol. 46, no. 5, pp. 1202-1209. https://doi.org/10.1002/art.10215
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. / Cyclosporine inhibition of vascular endothelial growth factor production in rheumatoid synovial fibroblasts. In: Arthritis and Rheumatism. 2002 ; Vol. 46, No. 5. pp. 1202-1209.
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AU - Cho, Mi La

AU - Cho, Chul Soo

AU - Min, So Youn

AU - Kim, Seung Hoon

AU - Lee, Shin Seok

AU - Kim, Wan Uk

AU - Min, Do June

AU - Min, Jun Ki

AU - Youn, Jeehee

AU - Hwang, Sue Yun

AU - Park, Sung Hwan

AU - Kim, Ho Youn

PY - 2002

Y1 - 2002

N2 - 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.

AB - 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.

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