The receptor for advanced glycation end products is required for β-catenin stabilization in a chemical-induced asthma model

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Abstract

Background and Purpose

Cytoplasmic 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 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 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 Implications

RAGE was required for stabilization of β-catenin in TDI-induced asthma, identifying protective effects of RAGE blockade in this model.

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