Aberrantly activated EGFR contributes to enhanced IL-8 expression in COPD airways epithelial cells via regulation of nuclear FoxO3A.
Aberrantly activated EGFR contributes to enhanced IL-8 expression in COPD airways epithelial cells via regulation of nuclear FoxO3A.
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DOI：
10.1136/thoraxjnl-2012-201719
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发表时间：
2013-03
期刊：
影响因子：
10
通讯作者：
Sajjan US
中科院分区：
文献类型：
--
作者：
Ganesan S;Unger BL;Comstock AT;Angel KA;Mancuso P;Martinez FJ;Sajjan US
叉头转录因子O类（FoxO）3A是NF-κ B介导的趋化因子表达的负调节因子，其活性降低与慢性阻塞性肺疾病（COPD）的发病机制有关。以前，我们发现槲皮素可以减少COPD小鼠模型的肺部炎症。在此，我们研究了COPD人气道上皮细胞和COPD小鼠模型中FoxO 3A活化降低及其受槲皮素调节的机制。用槲皮素、LY 294002或厄洛替尼处理原发性COPD和正常人气道上皮细胞两周。通过ELISA测量IL-8。FoxO 3A，Akt，和表皮生长因子受体（EGFR）的磷酸化和细胞核FoxO 3A水平通过蛋白质印迹分析。在COPD小鼠模型中测定槲皮素对肺趋化因子表达、核FoxO 3A水平以及EGFR和Akt磷酸化的影响。与正常相比，COPD细胞显示出显著增加的IL-8，其与核FoxO 3A水平呈负相关。COPD支气管活检也显示细胞核FoxO 3A减少。COPD细胞中FoxO 3A的减少与EGFR、Akt和FoxO 3A的磷酸化增加相关，槲皮素、LY 294002或厄洛替尼处理增加了细胞核FoxO 3A，降低了IL-8和Akt、EGFR和FoxO 3A的磷酸化。与对照组相比，弹性蛋白酶/LPS暴露小鼠显示细胞核FoxO 3A减少，趋化因子增加以及EGFR和Akt的磷酸化。槲皮素治疗部分逆转了这些变化。在COPD气道中，异常的EGFR活性增加PI 3-激酶/Akt介导的FoxO 3A磷酸化，从而减少核FoxO 3A并增加趋化因子表达。槲皮素部分通过调节EGFR/PI 3-激酶/Akt活性恢复细胞核FoxO 3A并降低趋化因子表达。
Decreased activity of forkhead transcription factor class O (FoxO)3A, a negative regulator of NF-κB-mediated chemokine expression, is implicated in the pathogenesis of chronic obstructive pulmonary disease (COPD). Previously, we showed that quercetin reduces lung inflammation in a murine model of COPD. Here, we examined the mechanisms underlying decreased FoxO3A activation and its modulation by quercetin in COPD human airway epithelial cells and in a COPD mouse model. Primary COPD and normal human airway epithelial cells were treated with quercetin, LY294002 or erlotinib for two weeks. IL-8 was measured by ELISA. FoxO3A, Akt, and EGF receptor (EGFR) phosphorylation and nuclear FoxO3A levels were determined by Western blot analysis. Effects of quercetin on lung chemokine expression, nuclear FoxO3A levels and phosphorylation of EGFR and Akt were determined in COPD mouse model. Compared to normal, COPD cells showed significantly increased IL-8, which negatively correlated with nuclear FoxO3A levels. COPD bronchial biopsies also showed reduced nuclear FoxO3A. Decreased FoxO3A in COPD cells was associated with increased phosphorylation of EGFR, Akt and FoxO3A and treatment with quercetin, LY294002 or erlotinib increased nuclear FoxO3A and decreased IL-8 and phosphorylation of Akt, EGFR and FoxO3A, Compared to control, elastase/LPS-exposed mice showed decreased nuclear FoxO3A, increased chemokines and phosphorylation of EGFR and Akt. Treatment with quercetin partially reversed these changes. In COPD airways, aberrant EGFR activity increases PI 3-kinase/Akt-mediated phosphorylation of FoxO3A, thereby decreasing nuclear FoxO3A and increasing chemokine expression. Quercetin restores nuclear FoxO3A and reduces chemokine expression partly by modulating EGFR/PI 3-kinase/Akt activity.
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DOI：
10.1165/rcmb.2005-0259oc
发表时间：
2006-08-01
影响因子：
6.4
作者：
Baginski, Tomasz K.;Dabbagh, Karim;Swinney, David C.
通讯作者：
Swinney, David C.
前列腺癌进展过程中 FOXO3A 的失调。
影响因子：
5.2
作者：
Shukla S;Shukla M;Maclennan GT;Fu P;Gupta S
通讯作者：
Gupta S
影响因子：
--
作者：
Ludikhuize, J.;de Launay, D.;Reedquist, K. A.
通讯作者：
Reedquist, K. A.
影响因子：
32.4
作者：
Lin, L;Hron, JD;Peng, SL
通讯作者：
Peng, SL
DOI：
10.1164/rccm.200911-1673oc
发表时间：
2010-08-01
影响因子：
24.7
作者：
Schneider, Dina;Ganesan, Shyamala;Sajjan, Umadevi
通讯作者：
Sajjan, Umadevi