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.

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