期刊
BRITISH JOURNAL OF PHARMACOLOGY
卷 173, 期 17, 页码 2600-2613出版社
WILEY
DOI: 10.1111/bph.13539
关键词
-
资金
- National Natural Science Foundation of China [81270087, 81270089, 81300029, 81470228]
- Natural Science Foundation of Guangdong Province [S2013040013505, 2014A030310325, 2015A 030313236]
- Scientific and Technological Project of Guangdong Province [2016A020215117]
BACKGROUND AND PURPOSE Cytoplasmic retention of beta-catenin will lead to its nuclear translocation and subsequent interaction with the transcription factor TCF/LEF that regulates target gene expression. We have previously demonstrated aberrant expression of beta-catenin in a model of asthma induced by toluene diisocyanate (TDI). The aim of this study was to examine whether the receptor for advanced glycation end products (RAGE) can regulate beta-catenin expression in TDI-induced asthma. EXPERIMENTAL APPROACH Male BALB/c mice were sensitized and challenged with TDI to generate a chemically-induced asthma model. Inhibitors of RAGE, FPS-ZM1 and the RAGE antagonist peptide (RAP), were injected i.p. after each challenge. Airway resistance was measured in vivo and bronchoalveolar lavage fluid was analysed. Lungs were examined by histology and immunohistochemistry. Western blotting and quantitative PCR were also used. KEY RESULTS Expression of RAGE and of its ligands HMGB1, S100A12, S100B, HSP70 was increased in TDI-exposed lungs. These increases were inhibited by FPS-ZM1 or RAP. Either antagonist blunted airway reactivity, airway inflammation and goblet cell metaplasia, and decreased release of Th2 cytokines. TDI exposure decreased level of membrane beta-catenin, phosphorylated Akt (Ser473), inactivated GSK3 beta (Ser(9)), dephosphorylated beta-catenin at Ser(33)/(37)/Thr(41), which controls its cytoplasmic degradation, increased phosphorylated beta-catenin at Ser(552), raised cytoplasmic and nuclear levels of beta-catenin and up-regulated its targeted gene expression (MMP2, MMP7, MMP9, VEGF, cyclin D1, fibronectin), all of which were reversed by RAGE inhibition. CONCLUSION AND IMPLICATIONS RAGE was required for stabilization of beta-catenin in TDI-induced asthma, identifying protective effects of RAGE blockade in this model.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据