Phosphorylation of low density lipoprotein receptor-related protein 6 is involved in receptor for advanced glycation end product-mediated beta-catenin stabilization in a toluene diisocyanate-induced asthma model
Phosphorylation of low density lipoprotein receptor-related protein 6 is involved in receptor for advanced glycation end product-mediated beta-catenin stabilization in a toluene diisocyanate-induced asthma model
复制标题
甲苯二异氰酸酯诱导的哮喘模型中低密度脂蛋白受体相关蛋白 6 的磷酸化参与晚期糖基化终产物介导的 β-连环蛋白稳定受体
DOI：
10.1016/j.intimp.2018.03.037
复制
发表时间：
2018
影响因子：
5.6
通讯作者：
Cai Shaoxi
中科院分区：
文献类型：
--
作者：
Xiong Jing;Zhao Wenqu;Lin Yun;Yao Lihong;Huang Guohua;Yu Changhui;Dong Hangming;Xiao Guanhua;Zhao Haijin;Cai Shaoxi
背景我们在甲苯二异氰酸酯（TDI）诱导的小鼠哮喘模型中证实了晚期糖基化终产物受体（receptor for advanced glycation end products，ERK）/β-catenin轴在调节气道炎症和气道重塑中起重要作用。然而，β-catenin激活的确切机制仍不清楚。鉴于低密度脂蛋白受体相关蛋白6（Lrp 6）的磷酸化是介导经典wnt/β-catenin信号通路中β-catenin稳定的关键步骤，我们探讨了在TDI诱导的asthma.MethodsIn这项研究中，TDI诱导的小鼠哮喘模型产生，并与特定的抑制剂治疗的β-catenin稳定之间的可能关系。在体外，用TDI-人血清白蛋白（TDI-HSA）处理人支气管上皮细胞系16 HBE。结果在TDI诱导的小鼠哮喘模型和TDI-HSA处理的16 HBE细胞中，抑制β-catenin表达或敲低β-catenin表达均能降低β-catenin在细胞核内的聚集，并降低β-catenin相关靶基因（VEGF、MMP 9、TGF-β1）的表达。在16 HBE细胞中，沉默ERK可逆转TDI诱导的磷酸化ERK 1/2（p-ERK）和磷酸化Lrp 6（p-Lrp 6）的增加。细胞外信号调节激酶（ERK）1/2抑制剂U 0126预处理抑制TDI诱导的Lrp 6磷酸化。Lrp 6基因敲低可降低β-catenin的核转位及VEGF、MMP 9和TGF-β 1的表达。结论在TDI诱导的小鼠模型中，ERK/ERK轴调节Lrp 6的磷酸化，参与β-catenin的稳定。
BackgroundWe 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.MethodsIn 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.ResultsThe 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.ConclusionThese data suggested that the RAGE/ERK axis modulates Lrp6 phosphorylation, contributing to β-catenin stabilization in a TDI-induced murine model.