title: Epithelial-mesenchymal transition induced by biliary innate immunity contributes to the sclerosing cholangiopathy of biliary atresia.
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 quickly and completely induced a transformation of morphology as well as change from epithelial to mesenchymal features in cultured biliary epithelial cells. Immunohistochemistry revealed that biliary epithelial cells lining extrahepatic bile ducts and peribiliary glands in BA frequently show a lack of epithelial markers and an aberrant expression of vimentin. Moreover, the biliary epithelium showing sclerosing cholangitis expressed bFGF accompanied by bFGF-positive mononuclear cells. In conclusion, the EMT may contribute to the histogenesis of sclerosing cholangiopathy, and the biliary innate immune response to dsRNA viruses induces biliary epithelial cells to undergo EMT via the production of bFGF and the increased susceptibility to TGF-beta1 caused by the down-regulation of Bambi expression.
authors.affiliation: Department of Human Pathology, Kanazawa University Graduate School of Medicine, Kanazawa, Japan.
authors.forename: Kenichi
authors.initials: K
authors.lastname: Harada
authors.forename: Yasunori
authors.initials: Y
authors.lastname: Sato
authors.forename: Hiroko
authors.initials: H
authors.lastname: Ikeda
authors.forename: Kumiko
authors.initials: K
authors.lastname: Isse
authors.forename: Satoru
authors.initials: S
authors.lastname: Ozaki
authors.forename: Mio
authors.initials: M
authors.lastname: Enomae
authors.forename: Kazunori
authors.initials: K
authors.lastname: Ohama
authors.forename: Kazuyoshi
authors.initials: K
authors.lastname: Katayanagi
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kurumaya
authors.forename: Akira
authors.initials: A
authors.lastname: Matsui
authors.forename: Yasuni
authors.initials: Y
authors.lastname: Nakanuma
mesh_terms: D017734:Bile Ducts, Extrahepatic / Q000378:metabolism / Q000473:pathology; D001656:Biliary Atresia / Q000276:immunology* / Q000473:pathology; D002478:Cells, Cultured; D015209:Cholangitis, Sclerosing / Q000276:immunology* / Q000473:pathology; D004847:Epithelial Cells / Q000276:immunology*; D005260:Female; D016222:Fibroblast Growth Factor 2 / Q000378:metabolism; D006801:Humans; D007113:Immunity, Innate; D007124:Immunoenzyme Techniques; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D008648:Mesoderm / Q000276:immunology*; D011070:Poly I-C / Q000276:immunology; D012330:RNA, Double-Stranded / Q000276:immunology; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D000071999:S100 Calcium-Binding Protein A4; D009418:S100 Proteins / Q000378:metabolism; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000378:metabolism
chemical_list: C485671:BAMBI protein, human; D008565:Membrane Proteins; D012330:RNA, Double-Stranded; D000071999:S100 Calcium-Binding Protein A4; D009418:S100 Proteins; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors; D053773:Transforming Growth Factor beta1; D016222:Fibroblast Growth Factor 2; C077591:S100A4 protein, human; D011070:Poly I-C