C-jun N-terminal kinase (JNK) inhibitor, SP600125, blocks interleukin (IL)-6-induced vascular endothelial growth factor (VEGF) production: cyclosporine A partially mimics this inhibitory effect.
Angiogenesis is a common complication of organ-transplant rejection. One of the primary responsible molecules for enhanced angiogenesis is vascular endothelial growth factor (VEGF). Activated protein (AP)-1 is considered to play a key role in the transcription of VEGF. c-jun N-terminal kinase (JNK), one of the MAP kinase family members, plays a critical role in AP-1 activation. Thus, we tested the effect of a novel JNK inhibitor, SP600125, on VEGF production in fibroblasts. SP600125 significantly suppressed interleukin (IL)-6-induced production of VEGF in cultured fibroblasts. Cyclosporine A (CsA), a known in vitro anti-angiogenic reagent, partially mimicked this suppression. In fact, CsA suppressed IL-6-induced phosphorylation of JNK. The results indicate that although both SP600125 and CsA are anti-angiogenic by inhibiting VEGF production by way of a JNK-dependent pathway, the inhibitory effect was much stronger with the novel inhibitor of JNK than with CsA.
Naruishi
Koji
K
Department of Pathophysiology/Periodontal Science, Okayama University Graduate School of Medicine and Dentistry, Japan.
Nishimura
Fusanori
F
Yamada-Naruishi
Hisa
H
Omori
Kazuhiro
K
Yamaguchi
Mayumi
M
Takashiba
Shogo
S
D000873:Anthracenes / Q000494:pharmacology*; D002478:Cells, Cultured; D016572:Cyclosporine / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005347:Fibroblasts / Q000166:cytology / Q000276:immunology; D005881:Gingiva / Q000187:drug effects / Q000276:immunology / Q000502:physiology; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors*; D009389:Neovascularization, Pathologic / Q000517:prevention & control; D010766:Phosphorylation; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors / Q000235:genetics*; D000093242:Interleukin-6 Inhibitors
D000873:Anthracenes; D016572:Cyclosporine; D004791:Enzyme Inhibitors; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D042461:Vascular Endothelial Growth Factor A; D000093242:Interleukin-6 Inhibitors; C432165:pyrazolanthrone