Early growth response factor 1 is essential for cigarette smoke-induced MUC5AC expression in human bronchial epithelial cells
Early growth response factor 1 is essential for cigarette smoke-induced MUC5AC expression in human bronchial epithelial cells
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早期生长反应因子 1 对于香烟烟雾诱导的人支气管上皮细胞 MUC5AC 表达至关重要
DOI：
10.1016/j.bbrc.2017.06.014
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发表时间：
2017
影响因子：
3.1
通讯作者：
Chen Zhi-Hua
中科院分区：
文献类型：
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作者：
Wang Shao-Bin;Zhang Chao;Xu Xu-Chen;Xu Feng;Zhou Jie-Sen;Wu Yan-Ping;Cao Chao;Li Wen;Shen Hua-Hao;Cao Jiao-Fei;Chen Zhi-Hua
早期生长反应因子1 （Egr-1）是一种锌指转录因子，对多种细胞外刺激反应迅速。先前的研究表明，Egr-1通过调节吸烟诱导的自噬、细胞死亡和炎症在慢性阻塞性肺疾病（COPD）中发挥病理功能。然而，关于Egr-1在气道上皮中调节粘液产生的作用知之甚少。在本研究中，我们观察到香烟烟雾提取物（CSE）诱导人支气管上皮细胞（HBE）中Egr-1和MUC5AC的连续表达。敲低Egr-1显著减弱CSE诱导的MUC5AC产生，染色质免疫沉淀显示Egr-1在CSE刺激下转录结合MUC5AC启动子。同时，CSE增加了活化蛋白1 （AP-1）的两个亚基c-Jun和c-Fos的表达，这两个亚基也对CSE诱导的HBE细胞MUC5AC具有关键调控作用。CSE还诱导了Egr-1和AP-1的物理相互作用，Egr-1的敲低显著降低了CSE诱导的c-Fos和c-Jun的表达。此外，敲低c-Fos显著减弱了cse诱导的Egr-1与MUC5AC启动子的结合。这些数据综合起来表明，Egr-1可能通过与AP-1的相互作用和调节，对cse诱导的HBE细胞MUC5AC的产生至关重要，并再次强调靶向Egr-1作为COPD的新治疗策略。
Early growth response factor 1 (Egr-1) is a zinc finger transcription factor which responses rapidly to a variety of extracellular stimuli. Previous studies have suggested that Egr-1 exerts pathological functions in chronic obstructive pulmonary disease (COPD) by regulation of cigarette smoking-induced autophagy, cell death, and inflammation. However, little is known about the role of Egr-1 in regulation of mucus production in airway epithelium. In this study, we observed that cigarette smoke extract (CSE) induced a successive expression of Egr-1 and MUC5AC in human bronchial epithelial (HBE) cells. Knockdown of Egr-1 markedly attenuated CSE-induced MUC5AC production, and chromatin immunoprecipitation revealed that Egr-1 transcriptionally bound to MUC5AC promoter upon CSE stimulation. Concurrently, CSE increased the expression of c-Jun and c-Fos, two subunits of activator protein 1 (AP-1) which also critically regulates CSE-induced MUC5AC in HBE cells. CSE also induced a physical interaction of Egr-1 and AP-1, and knockdown of Egr-1 significantly decreased CSE-induced expression of c-Fos and c-Jun. Furthermore, knockdown of c-Fos remarkably attenuated the CSE-induced Egr-1 binding to MUC5AC promoter. These data taken together demonstrate that Egr-1 is essential for CSE-induced MUC5AC production in HBE cells likely through interaction with and modulation of AP-1, and re-emphasize targeting Egr-1 as a novel therapeutic strategy for COPD.