Polke Markus, Seiler Frederik, Lepper Philipp M, Kamyschnikow Andreas, Langer Frank, Monz Dominik, Herr Christian, Bals Robert, Beisswenger Christoph
1 Department of Internal Medicine V - Pulmonology, Allergology and Critical Care Medicine, Saarland University, Homburg, Germany.
2 Department of Thoracic and Cardiovascular Surgery, Saarland University, Homburg, Germany.
Innate Immun. 2017 May;23(4):373-380. doi: 10.1177/1753425917698032. Epub 2017 Mar 8.
Chronic diseases of the respiratory tract, such as cystic fibrosis, are associated with mucosal and systemic hypoxia. Innate immune functions of airway epithelial cells are required to prevent and control infections of the lung parenchyma. The transcription factor hypoxia-inducible factor 1α (HIF-1α) regulates cellular adaptation to low oxygen conditions. Here, we show that hypoxia and HIF-1α regulate innate immune mechanisms of cultured human bronchial epithelial cells (HBECs). Exposure of primary HBECs to hypoxia or the prolyl hydroxylase inhibitor dimethyloxaloylglycine (DMOG) resulted in a significantly decreased expression of inflammatory mediators (IL-6, IFN-γ-induced protein 10) in response to ligands for TLRs (flagellin, polyI:C) and Pseudomonas aeruginosa, whereas the expression of inflammatory mediators was not affected by hypoxia or DMOG in the absence of microbial factors. Small interfering RNA-mediated knockdown of HIF-1α in HBECs and in the bronchial epithelial cell line Calu-3 resulted in increased expression of inflammatory mediators. The inflammatory response was decreased in lungs of mice stimulated with inactivated P. aeruginosa under hypoxia. These data suggest that hypoxia suppresses the innate immune response of airway epithelial cells via HIF-1α.
诸如囊性纤维化之类的慢性呼吸道疾病与黏膜和全身缺氧有关。气道上皮细胞的固有免疫功能对于预防和控制肺实质感染至关重要。转录因子缺氧诱导因子1α（HIF-1α）调节细胞对低氧条件的适应。在此，我们表明缺氧和HIF-1α调节培养的人支气管上皮细胞（HBECs）的固有免疫机制。将原代HBECs暴露于缺氧环境或脯氨酰羟化酶抑制剂二甲基草酰甘氨酸（DMOG），会导致其在响应Toll样受体（TLR）配体（鞭毛蛋白、聚肌苷酸胞苷酸）和铜绿假单胞菌时炎症介质（IL-6、干扰素γ诱导蛋白10）的表达显著降低，而在没有微生物因子的情况下，缺氧或DMOG对炎症介质的表达没有影响。用小干扰RNA介导敲低HBECs和支气管上皮细胞系Calu-3中的HIF-1α会导致炎症介质表达增加。在缺氧条件下用灭活的铜绿假单胞菌刺激的小鼠肺部，炎症反应减弱。这些数据表明，缺氧通过HIF-1α抑制气道上皮细胞的固有免疫反应。
