Tacrolimus but not cyclosporine A enhances FGF-2-induced VEGF release in osteoblasts.
We previously reported that basic fibroblast growth factor (FGF-2) stimulates the release of vascular endothelial growth factor (VEGF) via p44/p42 mitogen-activated protein (MAP) kinase and stress-activated protein kinase/c-Jun N-terminal kinase (SAPK/JNK) in osteoblast-like MC3T3-E1 cells and that FGF-2-activated p38 MAP kinase negatively regulates VEGF release. In addition, p70 S6 kinase activated by FGF-2 negatively regulates VEGF release via SAPK/JNK. In the present study, we investigated the effects of tacrolimus (FK506) and cyclosporine A, well-known immunosuppressants, on the FGF-2-induced VEGF release in these cells. Tacrolimus, but not cyclosporine A which alone had no effect on VEGF basal levels, significantly enhanced FGF-2-stimulated VEGF release. Tacrolimus markedly enhanced FGF-2-induced phosphorylation of SAPK/JNK without affecting the phosphorylation of p44/p42 MAP or p38 MAP kinases. SP600125, a specific inhibitor of SAPK/JNK, reduced the amplification by tacrolimus of the FGF-2-induced VEGF release. The FGF-2-induced phosphorylation of p70 S6 kinase was suppressed by tacrolimus. These results strongly suggest that tacrolimus enhances FGF-2-stimulated VEGF release via up-regulation of SAPK/JNK through modulating p70 S6 kinase in osteoblasts.
Yamauchi
Junichi
J
Department of Pharmacology, Gifu University Graduate School of Medicine, Gifu 501-1194, Japan.
Takai
Shinji
S
Matsushima-Nishiwaki
Rie
R
Adachi
Seiji
S
Minamitani
Chiho
C
Natsume
Hideo
H
Mizutani
Jun
J
Otsuka
Takanobu
T
Takeda
Jun
J
Harada
Atsushi
A
Kozawa
Osamu
O
Tokuda
Haruhiko
H
D000818:Animals; D002478:Cells, Cultured; D016572:Cyclosporine / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D016222:Fibroblast Growth Factor 2 / Q000378:metabolism*; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D051379:Mice; D010006:Osteoblasts / Q000378:metabolism*; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000235:genetics / Q000378:metabolism; D016559:Tacrolimus / Q000494:pharmacology*; D015854:Up-Regulation; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*
D004791:Enzyme Inhibitors; D007166:Immunosuppressive Agents; D042461:Vascular Endothelial Growth Factor A; D016222:Fibroblast Growth Factor 2; D016572:Cyclosporine; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D048031:JNK Mitogen-Activated Protein Kinases; D016559:Tacrolimus