Division of Respiratory Medicine, Second Affiliated Hospital, Chongqing Medical University, No. 74, Linjiang Road, Yuzhong District, Chongqing 400010, China.
Exp Cell Res. 2013 Nov 1;319(18):2866-73. doi: 10.1016/j.yexcr.2013.08.009. Epub 2013 Aug 27.
Mucus overproduction is an important feature in patients with chronic inflammatory airway diseases. However, the regulatory mechanisms that mediate excessive mucin production remain elusive. Recently, the level of YKL-40, a chitinase-like protein, has been found to be significantly increased in chronic inflammatory airway diseases and has been shown to be associated with the severity of these diseases. In this study, we sought to explore the effect of YKL-40 on mucin5AC (MUC5AC) production in chronic inflammatory airway diseases and the potential signaling pathways involved in this process. We found that elevated YKL-40 levels increased the mRNA and protein expression of MUC5AC in a dose- and time-dependent manner, in association with the phosphorylation of extracellular signal-regulated kinase (ERK) and nuclear factor κB (NF-κB), reflecting their activation. These responses were significantly suppressed by the knockdown of protease-activating receptor 2 (PAR2) with specific small interfering RNA or the inhibitors of ERK and NF-κB. YKL-40-induced MUC5AC overproduction was also effectively attenuated by the inhibitor of focal adhesion kinase (FAK). Taken together, these results imply that YKL-40 can stimulate excessive MUC5AC production through PAR2- and FAK-mediated mechanisms.
黏液过度产生是慢性炎症性气道疾病患者的一个重要特征。然而，介导过度黏蛋白产生的调节机制仍不清楚。最近，壳聚糖酶样蛋白 YKL-40 的水平在慢性炎症性气道疾病中被发现显著增加，并与这些疾病的严重程度相关。在这项研究中，我们试图探讨 YKL-40 对慢性炎症性气道疾病中黏蛋白 5AC（MUC5AC）产生的影响，以及涉及该过程的潜在信号通路。我们发现，YKL-40 水平的升高以剂量和时间依赖的方式增加了 MUC5AC 的 mRNA 和蛋白表达，与细胞外信号调节激酶（ERK）和核因子 κB（NF-κB）的磷酸化有关，反映了它们的激活。这些反应被特异性小干扰 RNA 敲低蛋白酶激活受体 2（PAR2）或 ERK 和 NF-κB 的抑制剂显著抑制。YKL-40 诱导的 MUC5AC 过度产生也被粘着斑激酶（FAK）抑制剂有效抑制。总之，这些结果表明，YKL-40 可以通过 PAR2 和 FAK 介导的机制刺激过度的 MUC5AC 产生。
