The receptor for advanced glycation end products is required for beta-catenin stabilization in a chemical-induced asthma model
The receptor for advanced glycation end products is required for beta-catenin stabilization in a chemical-induced asthma model
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在化学诱导的哮喘模型中，高级糖基化终产物的受体是β-连环蛋白稳定所必需的
DOI：
10.1111/bph.13539
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发表时间：
2016
影响因子：
7.3
通讯作者：
Cai Shaoxi
中科院分区：
文献类型：
--
作者：
Yao Lihong;Zhao Haijin;Tang Haixiong;Liang Junjie;Liu Laiyu;Dong Hangming;Zou Fei;Cai Shaoxi
背景与目的β-catenin在细胞质内滞留后，可发生核转位，并与调控靶基因表达的转录因子TCF/LEF相互作用。我们之前已经证明了在甲苯二异氰酸酯（TDI）诱导的哮喘模型中β-连环蛋白的异常表达。本研究旨在探讨糖基化终末产物受体（receptor for advanced glycation end products，RECEPTOR）对TDI诱导的哮喘中β-catenin表达的调节作用。实验方法雄性BALB/c小鼠经TDI致敏并激发，建立化学诱导的哮喘模型。每次激发后，腹膜内注射β-内酰胺酶抑制剂FPS-ZM 1和β-内酰胺酶拮抗剂肽（RAP）。在体测定气道阻力并分析支气管肺泡灌洗液。采用组织学和免疫组织化学方法对肺组织进行观察。Key ResultsThe expression of HMGB1，S100A12，S100B，HSP70 in TDI-exposed lungs were increased in the lungs and its ligands HMGB1，S100A12，S100B，HSP70.这些增加被FPS-ZM 1或RAP抑制。两种拮抗剂均可减弱气道反应性、气道炎症和杯状细胞化生，并减少Th 2细胞因子的释放。TDI暴露降低了膜β-catenin水平、磷酸化Akt（Ser 473）、失活的GSK 3 β（Ser 9）、Ser 33/37/Thr 41的去磷酸化β-catenin（控制其细胞质降解）、Ser 552的磷酸化β-catenin增加、β-catenin的细胞质和细胞核水平升高并上调其靶基因表达（MMP 2，MMP 7，MMP 9，VEGF，cyclin D1，fibronectin），所有这些都被抑制β-catenin所逆转。结论和意义在TDI诱导的哮喘中，β-catenin的稳定需要β-catenin，确定阻断β-catenin对该模型的保护作用。
Background and PurposeCytoplasmic retention of β‐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 β‐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 β‐catenin expression in TDI‐induced asthma.Experimental ApproachMale 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 measuredin vivoand bronchoalveolar lavage fluid was analysed. Lungs were examined by histology and immunohistochemistry. Western blotting and quantitative PCR were also used.Key ResultsExpression 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 β‐catenin, phosphorylated Akt (Ser473), inactivated GSK3β (Ser9), dephosphorylated β‐catenin at Ser33/37/Thr41, which controls its cytoplasmic degradation, increased phosphorylated β‐catenin at Ser552, raised cytoplasmic and nuclear levels of β‐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 ImplicationsRAGE was required for stabilization of β‐catenin in TDI‐induced asthma, identifying protective effects of RAGE blockade in this model.