Department of Respiratory Medicine, the Second Affiliated Hospital, Chongqing University of Medical Science, Chongqing 400010, China.
Mol Cell Biochem. 2011 Dec;358(1-2):249-55. doi: 10.1007/s11010-011-0975-2. Epub 2011 Jul 20.
Mucus hypersecretion is a major manifestation in patients with chronic inflammatory airway diseases, and MUC5AC protein is a major component of airway mucus. Earlier studies have demonstrated that neutrophil elastase (NE), a serine protease, mainly produced by neutrophils, stimulates the production of MUC5AC from airway epithelial cells. The microRNA miR-146a has been linked to inflammatory diseases. However, the role of miR-146a in the NE-induced MUC5AC expression remains unclear. Here, we show that NE exerts a dose- and time-dependent induction of both MUC5AC and miR-146a in human bronchial epithelial cells (16HBE). Ectopic expression of miR-146a in 16HBE cells inhibited the stimulation of MUC5AC by NE, while, conversely, depletion of endogenous miR-146a enhanced the MUC5AC production. Knockdown of intrinsic miR-146a activated both c-Jun N-terminal kinase (JNK) and nuclear factor-kappaB (NF-κB) signaling pathways. Moreover, targeting JNK or NF-κB by specific chemical inhibitors blocked the upregulation of MUC5AC by miR-146a silencing. Taken together, our data highlight a negative feedback role for miR-146a in the control of MUC5AC production from airway epithelial cells stimulated by NE, which may be associated with the inactivation of JNK and NF-κB signaling.
黏液高分泌是慢性炎症性气道疾病患者的主要表现，MUC5AC 蛋白是气道黏液的主要成分。早期研究表明，中性粒细胞弹性蛋白酶（NE），一种主要由中性粒细胞产生的丝氨酸蛋白酶，刺激气道上皮细胞产生 MUC5AC。microRNA miR-146a 与炎症性疾病有关。然而，miR-146a 在 NE 诱导的 MUC5AC 表达中的作用尚不清楚。在这里，我们表明 NE 以剂量和时间依赖的方式诱导人支气管上皮细胞（16HBE）中 MUC5AC 和 miR-146a 的表达。在 16HBE 细胞中异位表达 miR-146a 抑制了 NE 对 MUC5AC 的刺激，而相反，内源性 miR-146a 的耗竭增强了 MUC5AC 的产生。内源性 miR-146a 的敲低激活了 c-Jun N 端激酶（JNK）和核因子-κB（NF-κB）信号通路。此外，特异性化学抑制剂靶向 JNK 或 NF-κB 阻断了 miR-146a 沉默对 MUC5AC 的上调。总之，我们的数据强调了 miR-146a 在控制 NE 刺激的气道上皮细胞中 MUC5AC 产生中的负反馈作用，这可能与 JNK 和 NF-κB 信号通路的失活有关。
