β-amyloid-induced apoptosis is associated with cyclooxygenase-2 up-regulation via the mitogen-activated protein kinase-NF-κB signaling pathway
β-amyloid-induced apoptosis is associated with cyclooxygenase-2 up-regulation via the mitogen-activated protein kinase-NF-κB signaling pathway
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DOI：
10.1016/j.freeradbiomed.2005.02.023
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发表时间：
2005-06-15
影响因子：
7.4
通讯作者：
Surh, YJ
中科院分区：
文献类型：
--
作者：
Jang, JH;Surh, YJ
炎症性细胞死亡以及氧化应激已被牵连在一些神经退行性疾病，如阿尔茨海默病（AD）。环氧合酶-2（考克斯-2）的表达和胡萝卜素的产生在AD中经常升高。在这项研究中，我们研究了β-淀粉样蛋白（A β）诱导的炎症细胞死亡的分子机制，A β是一种神经毒性肽，在AD患者大脑中形成的老年斑中积累。A β处理的大鼠嗜铬细胞瘤（PC 12）细胞表现出考克斯-2的mRNA和蛋白表达增加，前列腺素E-2（PGE（2））的产生增加，并通过原位末端标记阳性、线粒体膜电位降低、Bax/Bcl-X-L比值增加、c-Jun N-末端激酶激活和聚（ADP-核糖）聚合酶裂解确定发生凋亡性死亡。塞来昔布（一种选择性考克斯-2抑制剂）预处理可减弱A β诱导的细胞死亡，而加入考克斯-2产物PGE可加重A β诱导的细胞死亡（2）。A β瞬时诱导氧化还原敏感性转录因子NF-κ B的活化，用NF-κ B抑制剂预处理PC 12细胞可消除A β诱导的考克斯-2表达。细胞外信号调节激酶（ERK）和p38丝裂原活化蛋白激酶（p38 MAPK）的药理学抑制以及这两种酶的显性负突变不仅抑制A β诱导的NF-κ B反式激活，而且抑制考克斯-2表达和PGE（2）产生。上述结果表明，A β诱导的PC 12细胞凋亡与考克斯-2通过激活NF-κ B上调有关，这是由上游激酶包括ERK和p38 MAPK介导的。(c)2005年爱思唯尔公司All rights reserved.
Inflammatory cell death as well as oxidative stress has been implicated in some neurodegenerative disorders such as Alzheimer's disease (AD). Expression of cyclooxygenase-2 (COX-2) and production of prostaglandins have been frequently elevated in AD. In this study, we have investigated the molecular mechanisms underlying inflammatory cell death induced by beta-amyloid (A beta), a neurotoxic peptide that accumulates in senile plaques formed in the brains of AD patients. Rat pheochromocytoma (PC12) cells treated with A beta exhibited increased mRNA and protein expression of COX-2 and production of prostaglandin E-2 (PGE(2)) and underwent apoptotic death as determined by positive in situ terminal end-labeling, decreased mitochondrial membrane potential, increased Bax/Bcl-X-L ratio, activation of c-Jun N-terminal kinase, and cleavage of poly(ADP-ribose)polymerase. Pretreatment with celecoxib, a selective COX-2 inhibitor, attenuated A beta-induced cell death, which was aggravated by addition of the COX-2 product PGE(2). A beta transiently induced activation of redox-sensitive transcription factor NF-kappa B, and pretreatment of PC12 cells with NF-kappa B inhibitors abolished the A beta-induced COX-2 expression. Pharmacologic inhibition of extracellular signal-regulated kinase (ERK) and p38 mitogen-activated protein kinase (p38 MAPK) and dominant-negative mutation of both enzymes suppressed not only A beta-induced NF-kappa B transactivation but also COX-2 expression and PGE(2) production. The above findings suggest that A beta-induced apoptosis in PC12 cells is associated with COX-2 up-regulation through activation of NF-kappa B, which is mediated by upstream kinases including ERK and p38 MAPK. (c) 2005 Elsevier Inc. All rights reserved.