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


CONCLUSIONS
CSA may exert an antiangiogenic effect by inhibiting AP-1-mediated VEGF expression in rheumatoid synovial fibroblasts.
The Center for Rheumatic Diseases in Kangnam St. Mary's Hospital, and Research Institute of Immunobiology, Catholic Research Institutes of Medical Sciences, Catholic University of Korea, Seoul, Korea.
Mi-La
ML
Cho
Chul-Soo
CS
Cho
So-Youn
SY
Min
Seung-Hoon
SH
Kim
Shin-Seok
SS
Lee
Wan-Uk
WU
Kim
Do-June
DJ
Min
Jun-Ki
JK
Min
Jeehee
J
Youn
Sue-Yun
SY
Hwang
Sung-Hwan
SH
Park
Ho-Youn
HY
Kim
D018501:Antirheumatic Agents / Q000494:pharmacology*; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000378:metabolism; D016572:Cyclosporine / Q000494:pharmacology*; D015536:Down-Regulation / Q000187:drug effects; D016228:Endothelial Growth Factors / Q000235:genetics*; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects* / Q000502:physiology; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology; D008222:Lymphokines / Q000235:genetics*; D011485:Protein Binding / Q000187:drug effects; D012333:RNA, Messenger / Q000032:analysis; D013583:Synovial Membrane / Q000166:cytology*; D016559:Tacrolimus / Q000494:pharmacology; D018808:Transcription Factor AP-1 / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
D018501:Antirheumatic Agents; D016228:Endothelial Growth Factors; D007166:Immunosuppressive Agents; D008222:Lymphokines; D012333:RNA, Messenger; D018808:Transcription Factor AP-1; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D016572:Cyclosporine; D000242:Cyclic AMP; D016559:Tacrolimus