磷酸化低密度脂蛋白受体相关蛋白 6 参与甲苯二异氰酸酯诱导的哮喘模型中晚期糖基化终产物受体介导的β-连环蛋白稳定化。
Phosphorylation of low density lipoprotein receptor-related protein 6 is involved in receptor for advanced glycation end product-mediated β-catenin stabilization in a toluene diisocyanate-induced asthma model.
机构信息
Chronic Airways Diseases Laboratory, Department of Respiratory and Critical Care Medicine, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China.
Chronic Airways Diseases Laboratory, Department of Respiratory and Critical Care Medicine, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China.
出版信息
Int Immunopharmacol. 2018 Jun;59:187-196. doi: 10.1016/j.intimp.2018.03.037. Epub 2018 Apr 12.
BACKGROUND
We have previously demonstrated that the receptor for advanced glycation end products (RAGE)/β-catenin axis plays a vital role in regulating airway inflammation and airway remodeling in a toluene diisocyanate (TDI)-induced murine asthma model. However, the exact mechanism of β-catenin activation remains unclear. Given that phosphorylation of the low-density lipoprotein receptor-related protein 6 (Lrp6) is a key step in mediating β-catenin stabilization in canonical wnt/β-catenin signaling, we explored the possible relationship between RAGE and Lrp6 in regulating β-catenin stabilization in TDI-induced asthma.
METHODS
In this study, a TDI-induced murine asthma model was generated, and mice were treated with a specific inhibitor of RAGE. In vitro, the human bronchial epithelial cell line 16HBE was treated with TDI-human serum albumin (TDI-HSA). RAGE overexpression or knockdown cells were also constructed and assessed.
RESULTS
The results showed that RAGE inhibition or RAGE knockdown decreased β-catenin nuclear accumulation and the expression of relevant β-catenin targeted genes (VEGF, MMP9, TGF-β1) in the TDI-induced murine asthma model and TDI-HSA-treated 16HBE cells, respectively. Silencing of RAGE reversed the TDI-induced increase in phospho-ERK1/2 (p-ERK) and phospho-Lrp6 (p-Lrp6) in 16HBE cells. Pretreatment with the extracellular signal-regulated kinase (ERK)1/2 inhibitor U0126 suppressed TDI-induced Lrp6 phosphorylation. Furthermore, knockdown of Lrp6 in 16HBE cells decreased β-catenin nuclear translocation and the expression of VEGF, MMP9, and TGF-β1.
CONCLUSION
These data suggested that the RAGE/ERK axis modulates Lrp6 phosphorylation, contributing to β-catenin stabilization in a TDI-induced murine model.
背景
我们之前已经证明，晚期糖基化终产物（RAGE）/β-连环蛋白轴在甲苯二异氰酸酯（TDI）诱导的哮喘小鼠模型中调节气道炎症和气道重塑方面发挥着重要作用。然而，β-连环蛋白激活的确切机制尚不清楚。鉴于低密度脂蛋白受体相关蛋白 6（Lrp6）的磷酸化是经典 Wnt/β-连环蛋白信号传导中稳定β-连环蛋白的关键步骤，我们探讨了 RAGE 与 Lrp6 之间在调节 TDI 诱导的哮喘中β-连环蛋白稳定化方面的可能关系。
方法
在这项研究中，我们建立了 TDI 诱导的哮喘小鼠模型，并使用 RAGE 的特异性抑制剂对其进行处理。体外，我们用 TDI-人血清白蛋白（TDI-HSA）处理人支气管上皮细胞系 16HBE。还构建并评估了 RAGE 过表达或敲低细胞。
结果
结果表明，RAGE 抑制或 RAGE 敲低分别降低了 TDI 诱导的哮喘小鼠模型和 TDI-HSA 处理的 16HBE 细胞中β-连环蛋白核积累和相关β-连环蛋白靶基因（VEGF、MMP9、TGF-β1）的表达。在 16HBE 细胞中沉默 RAGE 可逆转 TDI 诱导的磷酸化 ERK1/2（p-ERK）和磷酸化 Lrp6（p-Lrp6）的增加。预先用细胞外信号调节激酶（ERK）1/2 抑制剂 U0126 处理可抑制 TDI 诱导的 Lrp6 磷酸化。此外，在 16HBE 细胞中敲低 Lrp6 可减少β-连环蛋白核易位和 VEGF、MMP9 和 TGF-β1 的表达。
结论
这些数据表明，RAGE/ERK 轴调节 Lrp6 磷酸化，有助于 TDI 诱导的小鼠模型中β-连环蛋白的稳定化。
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