Tumor necrosis factor-α induction of endothelial ephrin A1 expression is mediated by a p38 MAPK- and SAPK/JNK-dependent but nuclear factor-κB-independent mechanism
Tumor necrosis factor-α induction of endothelial ephrin A1 expression is mediated by a p38 MAPK- and SAPK/JNK-dependent but nuclear factor-κB-independent mechanism
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DOI：
10.1074/jbc.m009147200
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发表时间：
2001-04-27
影响因子：
4.8
通讯作者：
Chen, J
中科院分区：
文献类型：
--
作者：
Cheng, N;Chen, J
肿瘤坏死因子-α（TNF-α）是一种多功能细胞因子，可诱导包括血管生成在内的广泛反应。由TNF-α促进的血管生成至少部分地由ephrin A1介导，ephrin A1是Eph受体酪氨酸激酶配体家族的成员。尽管TNF-α诱导内皮细胞中的ephrin A1表达，但介导ephrin A1诱导的信号通路仍然未知。在这项研究中，我们研究了内皮细胞中TNF-α依赖性诱导ephrin A1的信号转导机制。TNFR 1和TNFR 2似乎都参与调节内皮细胞中的肝配蛋白A1表达，因为TNFR 1或TNFR 2的中和抗体抑制TNF-α诱导的肝配蛋白A1表达。抑制核因子-κ B（NF-κ B）激活的突变体I κ B α的反式显性抑制亚型没有影响肝配蛋白A1的诱导，表明NF-κ B蛋白不是肝配蛋白A1表达的主要调节因子。相反，使用选择性化学抑制剂或显性负性形式的p88 MAPK或TNF受体相关因子2，抑制p38丝裂原活化蛋白激酶（MAPK）或SAPK/ JNK，而不是p42/44 MAPK，可以阻断ephrin A1的诱导。这些发现表明TNF-α诱导的ephrin A1表达是通过JNK和p38 MAPK信号通路介导的。总之，我们的研究结果表明，在内皮细胞中，TNF-α诱导ephrin A1是通过p38 MAPK和SAPK/JNK介导的，而不是p42/44 MAPK或NF-κ B途径。
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 investigated the signaling mechanisms of TNF-alpha -dependent induction of ephrin A1 in endothelial cells. Both TNFR1 and TNFR2 appear to be involved in regulating ephrin A1 expression in endothelial cells, because neutralizing antibodies to either TNFR1 or TNFR2 inhibited TNF-alpha induced ephrin A1 expression. Inhibition of nuclear factor-kappaB (NF-kappaB) activation by a trans-dominant 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 inhibition of p38 mitogen-activated protein kinase (MAPK) or SAPK/ JNK, but not p42/44 MAPK, using either selective chemical inhibitors or dominant-negative forms of p88 MAPK or TNF receptor-associated factor 2, These findings indicate that TNF-alpha -induced ephrin A1 expression is mediated through JNK and p38 MAPK signaling pathways. Taken together, the results of our study demonstrated that induction of ephrin A1 in endothelial cells by TNF-alpha is mediated through both p38 MAPK and SAPK/JNK, but not p42/44 MAPK or NF-kappaB, pathways.