Ceramide induces MMP-9 expression through JAK2/STAT3 pathway in airway epithelium
Ceramide induces MMP-9 expression through JAK2/STAT3 pathway in airway epithelium
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神经酰胺通过 JAK2/STAT3 通路诱导气道上皮 MMP-9 表达
DOI：
10.1186/s12944-020-01373-w
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发表时间：
2020-08
影响因子：
4.5
通讯作者：
Lihong Liu
中科院分区：
文献类型：
--
作者：
Lingling Xuan;Feifei Han;Lili Gong;Yali Lv;Zirui Wan;He Liu;Lulu Ren;Song Yang;Wen Zhang;Ting Li;Chunting Tan;Lihong Liu
研究背景神经酰胺是一种生物活性脂质，在多种肺部炎症性疾病的发生发展中起重要作用。基质金属肽酶9(Matrix Metallopeptidase 9，MMP9)调节细胞外基质的合成和降解，与呼吸道重构和组织损伤有关。方法用选择性Janus酪氨酸激酶2(JAK2)抑制剂AG490或选择性信号转导与转录激活剂3(STAT3)抑制剂STAT3处理BEAS-2B细胞，观察神经酰胺对MMP9表达的影响及其机制。然后用C6-神经酰胺刺激细胞。采用ELISA法和实时定量聚合酶链式反应(RT-qPCR法)检测基质金属蛋白酶-9水平。Western blotting检测JAK2、磷酸化JAK2(p-JAK2)、STAT3和磷酸化STAT3(p-STAT3)的表达。BALB/c小鼠在气管内注入C6-神经酰胺之前，先用AG490或STATTIC进行预处理。苏木精-伊红染色、周期-酸性席夫染色、Masson‘s三色染色观察肺组织病理变化。结果C6神经酰胺作用后，BEAS-2B细胞中MMP9、p-JAK2、p-JAK2、STAT3和p-STAT3的表达明显增加。此外，AG490和他汀类药物可抑制C6-神经酰胺诱导的基质金属蛋白酶-9表达增加。在给予AG490或他汀类药物治疗的C6神经酰胺暴露小鼠的肺组织中也得到了类似的结果。结论神经酰胺可通过激活呼吸道上皮细胞JAK2/STAT3通路上调MMP9的表达。靶向调控神经酰胺信号通路可能为抑制基质金属蛋白酶-9的表达提供一种潜在的治疗途径。这项研究指出了一种潜在的新方法来减轻炎症性呼吸道疾病的气道重塑。
BackgroundCeramide, a bioactive lipid, plays an essential role in the development of several pulmonary inflammatory diseases. Matrix metallopeptidase 9 (MMP-9) regulates the synthesis and degradation of extracellular matrix, and is associated with airway remodeling and tissue injury. This study was conducted to investigate the effects and underlying mechanisms of ceramide on MMP-9 expression in airway epithelium.MethodsBEAS-2B cells, normal human bronchial epithelium cell lines, were pretreated with AG490, a selective janus tyrosine kinase 2 (JAK2) inhibitor, or Stattic, a selectivesignal transducer and activator of transcription 3(STAT3) inhibitor. The cells were then stimulated with C6-ceramide. The levels of MMP-9 were determined by ELISA and real-time quantitative PCR (RT-qPCR). JAK2, phosphorylated JAK2 (p-JAK2), STAT3, and phosphorylated STAT3 (p-STAT3) expression was examined by Western blotting. BALB/c mice were pretreated with AG490 or Stattic before intratracheally instillated with C6-ceramide. Pathological changes in lung tissues were examined by Hematoxylin and Eosin staining, Periodic-acid Schiff staining, and Masson’s trichrome staining. MMP-9, JAK2, p-JAK2, STAT3, and p-STAT3 expression in the lung tissues was examined by Western blotting.ResultsThe expression of MMP-9, p-JAK2 and p-STAT3 in BEAS-2B cells was significantly increased after the treatment of C6-ceramide. Furthermore, the increased expression of MMP-9 induced by C6-ceramide was inhibited by AG490 and Stattic. Similar results were obtained in the lung tissues of C6-ceramide-exposed mice which were treated with AG490 or Stattic.ConclusionsCeramide could up-regulate MMP-9 expression through the activation of the JAK2/STAT3 pathway in airway epithelium. Targeted modulation of the ceramide signaling pathway may offer a potential therapeutic approach for inhibiting MMP-9 expression. This study points to a potentially novel approach to alleviating airway remodeling in inflammatory airway diseases.
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影响因子：
5.3
作者：
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影响因子：
8.2
作者：
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DOI：
10.1152/ajplung.00448.2007
发表时间：
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作者：
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