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Πέμπτη 12 Απριλίου 2018

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

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Publication date: June 2018
Source:International Immunopharmacology, Volume 59
Author(s): Jing Xiong, Wenqu Zhao, Yun Lin, Lihong Yao, Guohua Huang, Changhui Yu, Hangming Dong, Guanhua Xiao, Haijin Zhao, Shaoxi Cai
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.



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