Leptin positively regulates MUC5AC production and secretion induced by interleukin-13 in human bronchial epithelial cells
Leptin positively regulates MUC5AC production and secretion induced by interleukin-13 in human bronchial epithelial cells
复制标题
瘦素正向调节人支气管上皮细胞中白细胞介素13诱导的MUC5AC产生和分泌
DOI：
10.1016/j.bbrc.2017.09.106
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发表时间：
2017-11-18
影响因子：
3.1
通讯作者：
Han, Wei
中科院分区：
文献类型：
--
作者：
Hao, Wanming;Wang, Jing;Han, Wei
长期以来，粘液高分泌和粘液栓引起的下呼吸道阻塞被认为是哮喘发病和死亡的主要原因。MUC 5AC蛋白是气道粘液的主要成分。在这里，我们表明，白细胞介素（IL）-13诱导MUC 5AC的生产和分泌，瘦素表达在人支气管上皮细胞系-16（HBE 16）细胞中的浓度依赖性方式。瘦素敲低抑制IL-13诱导的MUC 5AC产生和分泌。我们进一步研究了瘦素发挥作用的分子机制，发现瘦素通过JAK 2-STAT 3途径调节IL-13诱导的MUC 5AC的产生和分泌。随后，发现气道上皮细胞和肥大细胞的胞吐机制的限制性组分Muncl 8b在敲低时，MUC 5AC分泌被显著抑制。SABiosciences ChIP搜索工具鉴定了具有Muncl 8b启动子的三个STAT 3结合位点。染色质免疫沉淀分析进一步证实Stat 3通过直接结合其启动子上调Muncl 8b表达。提示瘦素通过JAK 2-STAT 3-MUC 18 b调控网络促进MUC 5AC的分泌。总之，我们的数据突出了瘦素在控制IL-13刺激的气道上皮细胞产生和分泌MUC 5AC中的正反馈作用和分子机制，这鼓励进一步探索操纵瘦素在慢性炎症性肺病中治疗粘液高分泌的治疗潜力。(C)2017爱思唯尔公司All rights reserved.
Mucus hypersecretion and plugging of lower respiratory tract airways due to mucus plugs have long been recognized as the leading cause of the morbidity and mortality in asthma. MUC5AC protein is a major component of airway mucus. Here, we showed that interleukin (IL)-13 induced MUC5AC production and secretion, and leptin expression in the human bronchial epithelial cell line-16 (HBE16) cells in a concentration-dependent manner. Leptin knockdown suppressed MUC5AC production and secretion induced by IL-13. We further investigated the molecular mechanism by which leptin functioned, and found that leptin regulated IL-13-induced MUC5AC production and secretion via the JAK2-STAT3 pathway. Subsequently, Muncl8b, a limiting component of the exocytic machinery of airway epithelial and mast cells, was found that when knockdown, MUC5AC secretion was significantly inhibited. SABiosciences ChIP search tool identified three STAT3 binding sites with Muncl8b promoter. Chromatin immunoprecipitation analysis further confirmed that Stat3 upregulated Muncl8b expression by directly binding to its promoter. These data suggested that leptin promotes MUC5AC secretion via JAK2-STAT3-MUNC18b regulatory network. Taken together, our data highlight a positive feedback role and molecular mechanism for leptin in the control of MUC5AC production and secretion from airway epithelial cells stimulated by IL-13, which encourage further exploration of the therapeutic potentials of manipulating leptin in the treatment of mucus hypersecretion in chronic inflammation lung diseases. (C) 2017 Elsevier Inc. All rights reserved.