Zhang L, Himi T, Morita I, Murota S
Department of Cellular Physiological Chemistry, Graduate School, Tokyo Medical and Dental University 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8549, Japan.
Cell Death Differ. 2001 May;8(5):528-36. doi: 10.1038/sj.cdd.4400838.
Bovine carotid artery endothelial (BAE) cells are resistant to tumor necrosis factor-alpha (TNF), like most other cells. We examined if mitogen-activated protein (MAP) kinase and phosphatidylinositol-3 (PI3) kinase/Akt pathways are involved in this effect. In BAE cells, TNF activates MAP kinase in a MAP kinase kinase 1 (MEK1) manner and Akt in PI3-kinase-dependent manner. Pretreatment with either the MEK1 inhibitor U0126 or PI3-kinase inhibitor LY294002 sensitized BAE cells to TNF-induced apoptosis. Neither U0126 nor LY294002 pretreatment affected TNF-induced activation of NF-kappaB, suggesting that the MAP kinase or PI3-kinase/Akt-mediated anti-apoptotic effect induced by TNF was not relevant to NF-kappaB activation. Both MAP kinase and PI3-kinase/Akt -mediated signaling could prevent cytochrome c release and mitochondrial transmembrane potential (Deltapsi) decrease. PI3-kinase/Akt signaling attenuated caspase-8 activity, whereas MAP kinase signaling impaired caspase-9 activity. These results suggest that TNF-induced MAP kinase and PI3-kinase/Akt signaling play important roles in protecting BAE cells from TNF cytotoxicity.
与大多数其他细胞一样，牛颈动脉内皮（BAE）细胞对肿瘤坏死因子-α（TNF）具有抗性。我们研究了丝裂原活化蛋白（MAP）激酶和磷脂酰肌醇-3（PI3）激酶/Akt信号通路是否参与了这一效应。在BAE细胞中，TNF以MAP激酶激酶1（MEK1）依赖的方式激活MAP激酶，并以PI3激酶依赖的方式激活Akt。用MEK1抑制剂U0126或PI3激酶抑制剂LY294002预处理可使BAE细胞对TNF诱导的凋亡敏感。U0126或LY294002预处理均不影响TNF诱导的NF-κB激活，这表明TNF诱导的MAP激酶或PI3激酶/Akt介导的抗凋亡效应与NF-κB激活无关。MAP激酶和PI3激酶/Akt介导的信号传导均可阻止细胞色素c释放和线粒体跨膜电位（Δψ）降低。PI3激酶/Akt信号传导减弱了半胱天冬酶-8的活性，而MAP激酶信号传导则损害了半胱天冬酶-9的活性。这些结果表明，TNF诱导的MAP激酶和PI3激酶/Akt信号传导在保护BAE细胞免受TNF细胞毒性方面发挥着重要作用。
