Pseudomonas aeruginosa pyocyanin activates NRF2-ARE-mediated transcriptional response via the ROS-EGFR-PI3K-AKT/MEK-ERK MAP kinase signaling in pulmonary epithelial cells.
Pseudomonas aeruginosa pyocyanin activates NRF2-ARE-mediated transcriptional response via the ROS-EGFR-PI3K-AKT/MEK-ERK MAP kinase signaling in pulmonary epithelial cells.
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DOI：
10.1371/journal.pone.0072528
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Lau GW
中科院分区：
文献类型：
--
作者：
Xu Y;Duan C;Kuang Z;Hao Y;Jeffries JL;Lau GW
呼吸道病原菌铜绿假单胞菌分泌的氧化还原活性绿脓素(PCN)可产生活性氧(ROS)，对肺上皮细胞造成氧化应激。核因子(红系衍生的2)样蛋白2(NRF2)通过与顺式作用的抗氧化反应元件(ARE)结合，诱导解毒酶和蛋白的表达，从而对ROS介导的细胞死亡提供保护。然而，NRF2和PCN介导的氧化应激之间的明确关系尚未在实验上建立。在本研究中，我们研究了PCN对肺上皮细胞NRF2-ARE反应的诱导作用。我们分析了PCN对培养的人呼吸道上皮细胞和慢性PCN暴露的小鼠模型中NRF2表达和核转位的影响。NRF2依赖的抗氧化酶的转录也被评估。此外，我们使用抑制剂来检测EGFR及其下游信号组件的参与，这些信号组件介导了PCN对NRF2-ARE的激活。PCN促进核内NRF2的积累，并激活ARE介导的抗氧化基因的转录。此外，PCN通过诱导EGFR-磷脂酰肌醇-3-激酶(PI3K)信号通路及其主要下游效应蛋白AKT和MEK1/2-ERK1/2 MAP激酶来激活NRF2。抑制EGFR-PI3K信号显著减弱PCN刺激的NRF2在细胞核内的积聚。我们首次证明了PCN介导的氧化应激激活了EGFR-PI3K-AKT/MEK1/2-ERK1/2 MAP激酶信号通路，导致NRF2核转位，并在肺上皮细胞中产生反应性。
The redox-active pyocyanin (PCN) secreted by the respiratory pathogen Pseudomonas aeruginosa generates reactive oxygen species (ROS) and causes oxidative stress to pulmonary epithelial cells. Nuclear factor (erythroid-derived 2)-like 2 (NRF2) confers protection against ROS-mediated cell death by inducing the expression of detoxifying enzymes and proteins via its binding to the cis-acting antioxidant response element (ARE). However, a clear relationship between NRF2 and PCN-mediated oxidative stress has not been established experimentally. In this study, we investigated the induction of NRF2-ARE response by PCN in the pulmonary epithelial cells. We analyzed the effect of PCN on NRF2 expression and nuclear translocation in cultured human airway epithelial cells, and in a mouse model of chronic PCN exposure. NRF2-dependent transcription of antioxidative enzymes was also assessed. Furthermore, we used inhibitors to examine the involvement of EGFR and its downstream signaling components that mediate NRF2-ARE-activation in response to PCN. PCN enhances the nuclear NRF2 accumulation and activates the transcription of ARE-mediated antioxidant genes. Furthermore, PCN activates NRF2 by inducing the EGFR-phosphoinositide-3-kinase (PI3K) signaling pathway and its main downstream effectors, AKT and MEK1/2-ERK1/2 MAP kinases. Inhibition of the EGFR-PI3K signaling markedly attenuates PCN-stimulated NRF2 accumulation in the nucleus. We demonstrate for the first time that PCN-mediated oxidative stress activates the EGFR-PI3K-AKT/MEK1/2-ERK1/2 MAP kinase signaling pathway, leading to nuclear NRF2 translocation and ARE responsiveness in pulmonary epithelial cells.
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影响因子：
3.8
作者：
Cho, Hye-Youn;Kleeberger, Steven R.
通讯作者：
Kleeberger, Steven R.
影响因子：
19.7
作者：
Farrell, Philip M.;Collins, Jannette;Brody, Alan S.
通讯作者：
Brody, Alan S.
DOI：
10.1165/ajrcmb.18.4.2959
发表时间：
1998-04-01
影响因子：
6.4
作者：
Ho, YS;Vincent, R;Crapo, JD
通讯作者：
Crapo, JD
影响因子：
4.8
作者：
Papaiahgari, S;Kleeberger, SR;Reddy, SP
通讯作者：
Reddy, SP
影响因子：
3.2
作者：
Gloyne, Lee S.;Grant, Gary D.;Anoopkumar-Dukie, Shailendra
通讯作者：
Anoopkumar-Dukie, Shailendra