Tumor necrosis factor-alpha induction of endothelial ephrin A1 expression is mediated by a p38 MAPK- and SAPK/JNK-dependent but nuclear factor-kappa B-independent mechanism

Tumor necrosis factor-alpha (TNF-alpha) is a multifunctional cytokine that induces a broad spectrum of responses including angiogenesis. Angiogenesis promoted by TNF-alpha is mediated, at least in part, by ephrin A1, a member of the ligand family for Eph receptor tyrosine kinases. Although TNF-alpha induces ephrin A1 expression in endothelial cells, the signaling pathways mediating ephrin A1 induction remain unknown. In this study, we investigate d the signaling mechanisms of TNF-alpha -dependent induction of ephrin A1 i n endothelial cells. Both TNFR1 and TNFR2 appear to be involved in regulati ng ephrin A1 expression in endothelial cells, because neutralizing antibodi es to either TNFR1 or TNFR2 inhibited TNF-alpha induced ephrin A1 expressio n. Inhibition of nuclear factor-kappaB (NF-kappaB) activation by a trans-do minant inhibitory isoform of mutant I kappaB alpha did not affect ephrin A1 induction, suggesting that NF-kappaB proteins are not major regulators of ephrin A1 expression. In contrast, ephrin A1 induction was blocked by inhib ition of p38 mitogen-activated protein kinase (MAPK) or SAPK/ JNK, but not p42/44 MAPK, using either selective chemical inhibitors or dominant-negativ e forms of p88 MAPK or TNF receptor-associated factor 2, These findings ind icate that TNF-alpha -induced ephrin A1 expression is mediated through JNK and p38 MAPK signaling pathways. Taken together, the results of our study d emonstrated that induction of ephrin A1 in endothelial cells by TNF-alpha i s mediated through both p38 MAPK and SAPK/JNK, but not p42/44 MAPK or NF-ka ppaB, pathways.