1α, 25-dihydroxyvitamin D3 inhibits transforming growth factor β1-induced epithelial-mesenchymal transition via β-catenin pathway

Background:The transforming growth factor beta 1 (TGF-beta 1)-induced epithelial-mesenchymal transition (EMT) has been proven associated with the pathogenesis of asthmatic airway remodeling, in which the Wnt/beta -catenin pathway plays an important role, notably with regard to TGF-beta 1. Recent studies have shown that 1 alpha, 25-dihydroxyvitamin D-3(1 alpha, 25(OH)(2)D-3) inhibits TGF-beta 1-induced EMT, although the underlying mechanism have not yet been fully elucidated.Methods:Alveolar epithelial cells were exposed to 1 alpha, 25(OH)(2)D-3, ICG-001, or a combination of both, followed by stimulation with TGF-beta 1. The protein expression of E-cadherin, alpha -smooth muscle actin, fibronectin, and beta -catenin was analyzed by western blotting and immunofluorescence analysis. The mRNA transcript of Snail was analyzed using RT-qPCR, and matrix metalloproteinase 9 (MMP-9) activity was analyzed by gelatin zymogram. The activity of the Wnt/beta -catenin signaling pathway was analyzed using the Top/Fop flash reporters.Results:Both 1 alpha, 25(OH)(2)D-3 and ICG-001 blocked TGF-beta 1-induced EMT in alveolar epithelial cells. In addition, the Top/Fop Flash reporters showed that 1 alpha, 25(OH)(2)D-3 suppressed the activity of the Wnt/beta -catenin pathway and reduced the expression of target genes, including MMP-9 and Snail, in synergy with ICG-001.Conclusion:1 alpha, 25(OH)(2)D-3 synergizes with ICG-001 and inhibits TGF-beta 1-induced EMT in alveolar epithelial cells by negatively regulating the Wnt/beta -catenin signaling pathway.