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Mycoplasma pneumoniae Modulates STAT3-STAT6/EGFR-FOXA2 Signaling To Induce Overexpression of Airway Mucins

机译:肺炎支原体调节STAT3-STAT6 / EGFR-FOXA2信号传导,导致气道粘蛋白过表达

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Aberrant mucin secretion and accumulation in the airway lumen are clinical hallmarks associated with various lung diseases such as asthma, chronic obstructive pulmonary disease, and cystic fibrosis. Mycoplasma pneumoniae, long appreciated as one of the triggers of acute exacerbations of chronic pulmonary diseases, has recently been reported to promote excessive mucus secretion. However, the mechanism of mucin overproduction induced by M. pneumoniae remains unclear. This study aimed to determine the mechanism by which M. pneumoniae induces mucus hypersecretion by using M. pneumoniae infection of mouse lungs, human primary bronchial epithelial (NHBE) cells cultured at the air-liquid interface, and the conventionally cultured airway epithelial NCI-H292 cell line. We demonstrated that M. pneumoniae induced the expression of mucins MUC5AC and MUC5B by activating the STAT6-STAT3 and epidermal growth factor receptor (EGFR) signal pathways, which in turn downregulated FOXA2, a transcriptional repressor of mucin biosynthesis. The upstream stimuli of these pathways, including interleukin-4 (IL-4), IL-6, and IL-13, increased dramatically upon exposure to M. pneumoniae. Inhibition of the STAT6, STAT3, and EGFR signaling pathways significantly restored the expression of FOXA2 and attenuated the expression of airway mucins MUC5AC and MUC5B. Collectively, these studies demonstrated that M. pneumoniae induces airway mucus hypersecretion by modulating the STAT/EGFR-FOXA2 signaling pathways.
机译:气管腔中粘蛋白的异常分泌和积累是与各种肺部疾病(例如哮喘,慢性阻塞性肺部疾病和囊性纤维化)相关的临床标志。长期以来,肺炎支原体一直被认为是慢性肺部疾病急性加重的诱因之一,最近已报道其可促进粘液分泌过多。然而,由肺炎支原体诱导的粘蛋白过量生产的机制仍不清楚。这项研究旨在确定肺炎支原体通过使用小鼠肺炎支原体感染,在气液界面上培养的人原代支气管上皮(NHBE)细胞和常规培养的气道上皮NCI-H292诱导粘液分泌过多的机制细胞系。我们证明肺炎支原体通过激活STAT6-STAT3和表皮生长因子受体(EGFR)信号通路,诱导粘蛋白MUC5AC和MUC5B的表达,进而下调了粘蛋白生物合成的转录抑制因子FOXA2。这些途径的上游刺激,包括白介素4(IL-4),IL-6和IL-13,在暴露于肺炎支原体后会急剧增加。抑制STAT6,STAT3和EGFR信号通路显着恢复FOXA2的表达并减弱气道粘蛋白MUC5AC和MUC5B的表达。这些研究共同表明,肺炎支原体通过调节STAT / EGFR-FOXA2信号传导途径诱导气道粘液分泌过多。

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