纺神星
Notch信号通路
炎症
细胞凋亡
DNA甲基化
基因沉默
下调和上调
癌症研究
信号转导
细胞生物学
程序性细胞死亡
槽口1
生物
免疫学
内分泌学
基因表达
生物化学
基因
肾
作者
Jie Qiu,Yanan Zhang,Xin Zheng,Peng Zhang,Gang Ma,Hai Tan
标识
DOI:10.1080/01902148.2018.1556749
摘要
Aim: Klotho expression significantly declines in alveolar macrophages and airway epithelial cells in chronic obstructive pulmonary disease (COPD) patients, and cigarette smoke extract dramatically inhibits the expression and secretion of α-Klotho. This suggests that the silencing of Klotho is the major factor promoting COPD related inflammatory responses. This study aims to investigate the mechanism of Klotho downregulation and its effect on the inflammatory cytokines secretion and cell apoptosis. Methods: Expression of DNA methyltransferases (DNMTs) and Notch signaling activation were quantified in MH-S and 16HBE cells stimulated with cigarette smoke extract (CSE) solution. Specific inhibitors of DNMTs or Notch pathway were added together with CSE into treated and control cells. Inflammatory cytokines, cell viability and cell death were determined to explore the effect of Klotho on COPD related inflammation. Results: CSE treatment statistically increased the level of DNMTs expression, Klotho promoter methylation, and activated the Notch signaling pathway. Notch signal activation played a critical role in the process of modification of Klotho promoter methylation. The inhibition of DNMTs and Notch pathway rescued Klotho levels and inhibited inflammation and cell apoptosis after CSE treatment. Conclusion: Notch-mediated Klotho hypermethylation inhibited Klotho expression, which promoted inflammatory response and cell apoptosis that were associated with the development of COPD.
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