Enterovirus 71 induces COX-2 expression via MAPKs, NF-κB, and AP-1 in SK-N-SH cells: Role of PGE2 in viral replication
Enterovirus 71 induces COX-2 expression via MAPKs, NF-κB, and AP-1 in SK-N-SH cells: Role of PGE2 in viral replication
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DOI：
10.1016/j.cellsig.2009.09.018
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发表时间：
2010-02-01
影响因子：
4.8
通讯作者：
Yang, Chuen-Mao
中科院分区：
文献类型：
--
作者：
Tung, Wei-Hsuan;Hsieh, Hsi-Lung;Yang, Chuen-Mao
肠道病毒71型（Enterovirus 71，EV 71）通过在脑内表达环氧合酶-2（cyclooxygenase-2，考克斯-2）而引起严重的神经系统疾病。然而，在神经元中，EV 71引发的导致考克斯-2表达的细胞内信号传导途径的潜在机制仍然未知。在此，我们报告了通过Western印迹实时PCR和PGE（2）分析显示，暴露于EV 71的SK-N-SH细胞以时间和病毒滴度依赖的方式增加了考克斯-2表达和PGE（2）生成。这些EV 71诱导的应答通过p42/p44 MAPK、p38 MAPK、JNK、NF-κ B和AP-1的活化介导，通过使用选择性药理学抑制剂或用各自的siRNA转染揭示。一致地，分别用MEK 1/2（U 0126）和NF-κ B（Bay 11 -7085）的选择性抑制剂预处理可阻断EV 71刺激的NF-κ B向细胞核的移位和胞质中I κ B α的降解，这表明与NF-κ B连接的MEK 1/2-p42/p44 MAPK级联参与考克斯-2表达。此外，用选择性JNK抑制剂SP 600125预处理也减弱了EV 71诱导的AP-1亚基（c-jun和c-fos mRNA）表达，表明连接AP-1的JNK级联参与了EV 71诱导的考克斯-2表达。提示考克斯-2的表达上调与PGE 2的释放有关，其机制可能与p38 MAPK、JNK、p42/p44 MAPK、NF-κ B B的活化有关。AP-1通路。(C)2009 Elsevier Inc. All rights reserved.
The enterovirus 71 (EV71) causes severe neurological diseases that were mediated through cyclooxygenase-2 (COX-2) expression in brain. However, the mechanisms underlying EV71-initiated intracellular signaling pathways leading to COX-2 expression remain unknown in neurons. Here we report that exposure of SK-N-SH cells to EV71 increased COX-2 expression and PGE(2) generation in a time- and virus titer-dependent manner, revealed by Western blots real-time PCR, and PGE(2) analyses. These EV71-induced responses were mediated through activation of p42/p44 MAPK, p38 MAPK, JNK, NF-kappa B, and AP-1, revealed by using selective pharmacological inhibitors or transfection with respective siRNAs. Consistently, EV71-stimulated translocation of NF-kappa B into the nucleus and degradation of I kappa B alpha in the cytosol was blocked by pretreatment with the selective inhibitors of MEK1/2 (U0126) and NF-kappa B (Bay11-7085), respectively, suggesting that MEK1/2-p42/p44 MAPK cascade linking to NF-kappa B was involved in COX-2 expression. In addition, EV71-induced AP-1 subunits (c-jun and c-fos mRNA) expression was also attenuated by pretreatment with a selective JNK inhibitor SP600125, suggesting that JNK cascade linking to AP-1 was involved in COX-2 expression induced by EV71. These findings suggested that up-regulation of COX-2 associated with the release of PGE2 from EV71-infected SK-N-SH cells which was mediated through activation of p38 MAPK, JNK, p42/p44 MAPK NF-kappa B. and AP-1 pathways. (C) 2009 Elsevier Inc. All rights reserved.