Epithelial-mesenchymal transition induced by biliary innate immunity contributes to the sclerosing cholangiopathy of biliary atresia
Epithelial-mesenchymal transition induced by biliary innate immunity contributes to the sclerosing cholangiopathy of biliary atresia
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DOI：
10.1002/path.2488
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发表时间：
2009-04-01
影响因子：
7.3
通讯作者：
Nakanuma, Yasuni
中科院分区：
文献类型：
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作者：
Harada, Kenichi;Sato, Yasunori;Nakanuma, Yasuni
由双链RNA(DsRNA)基因组组成的呼肠孤病毒科的感染和胆道对dsRNA的天然免疫反应与胆道闭锁(BA)的发病机制有关。近年来，上皮-间充质转化(EMT)被认为是BA硬化性胆管炎的机制。我们推测，胆管上皮细胞对dsRNA的先天免疫反应在通过胆道EMT导致的胆管周围纤维化中起重要作用。用培养的人胆管上皮细胞进行的实验表明，Poly(I：C)(一种病毒dsRNA的合成类似物)刺激增加了碱性成纤维细胞生长因子(碱性成纤维细胞生长因子，EMT诱导剂)、S100A4(间质标志物)和Snail(转录因子)的表达，降低了上皮标志物(胆汁型细胞角蛋白19和E-钙粘素)和Bambi(转化生长因子-β1假受体)的表达。多聚(I：Q)不影响转化生长因子β1(EMT诱导物)和波形蛋白(间质标志物)的表达。碱性成纤维细胞生长因子和转化生长因子β1分别诱导上皮标志物和波形蛋白的表达减少和增加，Bambi的表达在碱性成纤维细胞生长因子的刺激下被下调。联合应用碱性成纤维细胞生长因子和转化生长因子-β1可快速、完全地诱导培养的胆管上皮细胞发生形态转变以及由上皮样向间充质样转变。免疫组织化学结果显示，BA的胆管和胆周腺衬里的胆管上皮细胞常缺乏上皮标志物和波形蛋白的异常表达。此外，硬化性胆管炎的胆管上皮细胞表达bFGF，并伴有bFGF阳性的单核细胞。总之，EMT可能参与了硬化性胆管病的组织发生，胆汁对dsRNA病毒的先天免疫应答通过bFGF的产生和Bambi表达下调导致对转化生长因子-β1的敏感性增加而诱导胆管上皮细胞发生EMT。版权所有(C)2008年大不列颠和爱尔兰病理学会。作者：John Wiley&Sons，Ltd.
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-beta 1 pseudoreceptor). The expression of TGF-beta 1 (EMT-inducer) and vimentin (a mesenchymal marker) was not affected by poly(I: Q. Both EMT-inducers, bFGF and TGF-beta 1, 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-beta 1 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-beta 1 caused by the down-regulation of Bambi expression. Copyright (C) 2008 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.