Epithelial-mesenchymal transition induced by biliary innate immunity contributes to the sclerosing cholangiopathy of biliary atresia

The Journal of Pathology
Kenichi HaradaYasuni Nakanuma

Abstract

Infections of Reoviridae consisting of a double-stranded RNA (dsRNA) genome and the biliary innate immune response to dsRNA are implicated in the aetiopathogenesis of biliary atresia (BA). Epithelial-mesenchymal transition (EMT) has recently been proposed as a mechanism behind the sclerosing cholangitis in BA. We hypothesized that the innate immune response to dsRNA in biliary epithelial cells plays an important role in peribiliary fibrosis via biliary EMT. Experiments using cultured human biliary epithelial cells revealed that stimulation with poly(I : C) (a synthetic analogue of viral dsRNA) increased the expression of basic fibroblast growth factor (bFGF, an EMT-inducer), S100A4 (a mesenchymal marker) and Snail (a transcriptional factor), and decreased that of epithelial markers (biliary-type cytokeratin 19 and E-cadherin) and Bambi (TGF-beta1 pseudoreceptor). The expression of TGF-beta1 (EMT-inducer) and vimentin (a mesenchymal marker) was not affected by poly(I : C). Both EMT-inducers, bFGF and TGF-beta1, evoked a decrease and increase in the expression of the epithelial markers and of vimentin respectively, and the expression of Bambi was down-regulated on stimulation with bFGF. Combined treatment with bFGF and TGF-beta1 ...Continue Reading

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