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首页> 外文期刊>Biocell >FBXW7 regulates epithelial barrier impairment in human bronchial epithelial cells in vitro by targeting apoptosis signal-regulating kinase1 via the p38 pathway
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FBXW7 regulates epithelial barrier impairment in human bronchial epithelial cells in vitro by targeting apoptosis signal-regulating kinase1 via the p38 pathway

机译：通过P38途径靶向细胞凋亡信号调节激酶1，FBXW7在体外调节人支气管上皮细胞的上皮屏障损伤

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Bronchial asthma is a common chronic inflammatory disease characterized by airway hyperresponsiveness (AHR), inflammatory cell infiltration, and airway remodeling. F-box/WD repeat-containing protein 7 (FBXW7), an E3 ubiquitin ligase, is required for various endothelial functions, such as cell migration, inflammation, and endothelial integrity. This study aimed to investigate the role of FBXW7 in lipopolysaccharide (LPS)-induced epithelial barrier impairment in bronchial epithelial cells in vitro. By using lentivirus-based technology, FBXW7 was overexpressed or silenced (24 h) in human bronchial epithelial (16HBE) cells, which were treated with LPS or not (24 h). Immunoprecipitation (IP) detection and Western blot analysis were used to evaluate the interaction of target proteins. Cell permeability was measured using transepithelial electrical resistance and FITC dextran flux (48 h). IL-1β, IL-18 and TNF-α in cell supernatants were measured using ELISA (48 h). The results showed that LPS stimulation suppressed FBXW7 expression in a time- and dose-dependent manner. LPS exposure decreased cell proliferation, elevated IL-1β, IL-18 and TNF-α, increased epithelial permeability, and p38 phosphorylation. These LPS-induced changes were partly compromised by FBXW7 overexpression. Similar to LPS stimulation, FBXW7 knockdown increased epithelial permeability and levels of inflammatory cytokines and p38 phosphorylation, which were, in part, blocked by apoptosis signal-regulating kinase (ASK) 1 knockdown or p38 pathway inhibition. IP and Western blot analysis showed that FBXW7 interacted with ASK1. ASK1 expression was inversely associated with FBXW7 expression. FBXW7 overexpression markedly enhanced ASK1 ubiquitination. These data revealed that FBXW7 counter against inflammation and protects epithelial barrier integrity in bronchial epithelial cells by promoting ubiquitination-mediated degradation of ASK1 via the p38 pathway.
机译：支气管哮喘是一种常见的慢性炎症疾病，其特征在于气道高反应性（AHR），炎症细胞浸润和气道重塑。对于各种内皮功能，例如细胞迁移，炎症和内皮完整性，需要F型箱/ Wd含重复的蛋白质7（FBXW7），e3泛素连接酶。本研究旨在探讨FBXW7在体外支气管上皮细胞中的脂多糖（LPS）诱导的上皮屏障损伤的作用。通过使用基于慢病毒的技术，FBXW7过表达或沉默（24小时）在人支气管上皮（16HBE）细胞中，用LPS或不（24小时）处理。免疫沉淀（IP）检测和Western印迹分析用于评估靶蛋白的相互作用。使用Transepearial电阻和FITC葡聚糖通量（48小时）测量细胞渗透性。使用ELISA（48小时）测量细胞上清液中的IL-1β，IL-18和TNF-α。结果表明，LPS刺激以时间和剂量依赖的方式抑制FBXW7表达。 LPS曝光降低细胞增殖，升高的IL-1β，IL-18和TNF-α，上皮渗透性增加和P38磷酸化。这些LPS诱导的变化部分受到FBXW7过表达的影响。类似于LPS刺激，FBXW7敲低增加上皮渗透性和炎性细胞因子和P38磷酸化水平，部分地部分地由凋亡信号调节激酶（ASK）1敲低或P38途径抑制。 IP和Western印迹分析显示FBXW7与Ask1相互作用。 Ask1表达与FBXW7表达相反。 FBXW7过表达明显增强了Ask1泛素化。这些数据显示，通过通过P38途径促进泛素化介导的Ask1降解，FBXW7对抗炎症并保护支气管上皮细胞中的上皮阻挡完整性。

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