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 antiangiogenic 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.