Innate immune response to double-stranded RNA in biliary epithelial cells is associated with the pathogenesis of biliary atresia
Innate immune response to double-stranded RNA in biliary epithelial cells is associated with the pathogenesis of biliary atresia
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DOI：
10.1002/hep.21797
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发表时间：
2007-10-01
期刊：
影响因子：
13.5
通讯作者：
Nakanuma, Yasuni
中科院分区：
文献类型：
--
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是胆道闭锁（BA）的可能原因。本研究的目的是阐明双链RNA病毒在BA发病机制中的病理生理功能。在体外培养的人胆管上皮细胞（BECs）中组成型检测了dsRNA模式识别受体、Toll样受体3（TLR3）、视黄酸诱导基因I（RIG-I）、黑色素瘤分化相关基因5（MDA-5）和dsRNA激活的蛋白激酶R（PKR）的表达。用聚肌苷酸-聚胞苷酸[poly（I：C），病毒dsRNA的合成类似物]刺激诱导转录因子[核因子（NF）-κ B和干扰素调节因子3（IRF 3）]的活化以及干扰素β 1（IFN-β 1）和MxA的产生，作为有效的抗病毒应答。此外，poly（I：C）上调肿瘤坏死因子相关凋亡诱导配体（TRAIL）的表达，并且poly（I：C）和TRAIL均通过增强凋亡来降低培养的人BEC的活力。使用BA患者和对照组（胆总管囊肿和非胆道疾病）肝外胆管组织切片的体内实验表明，在BA中，NF-κ B、干扰素调节因子-3（IRF-3）和PKR的激活以及TRAIL和单链DNA（ssDNA）阳性细胞凋亡的增强是显著的，尽管在所有疾病中肝外胆管弥漫性且持续表达TLR3。结论：dsRNA病毒可以直接诱导人胆管上皮细胞中TRAIL的表达和细胞凋亡，作为胆道先天免疫应答的结果，支持呼肠孤病毒科感染与BA病例中胆管病的发病机制直接相关的观点。
Infections of Reoviridae consisting of a double-stranded RNA (dsRNA) genome are a possible cause of biliary atresia (BA). The aim of the present study is to clarify the pathophysiological function of dsRNA viruses in the pathogenesis of BA. The expression of dsRNA pattern-recognizing receptors, Toll-like receptor 3 (TLR3), retinoic acid inducible gene I (RIG-I), melanoma differentiation-associated gene-5 (MDA-5), and dsRNA-activated protein kinase R (PKR) was constitutively detected in cultured human biliary epithelial cells (BECs). Stimulation with polyinosinic-polycytidylic acid [poly(I:C), a synthetic analog of viral dsRNA] induced the activation of transcription factors [nuclear factor (NF)-kappa B and interferon regulatory factor 3 (IRF3)] and the production of interferon-/ss 1 (IFN-ss 1) and MxA as potent antiviral responses. Moreover, poly(I:C) up-regulated the expression of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), and both poly(I:C) and TRAIL reduced the viability of cultured human BECs by enhancing apoptosis. Experiments in vivo using tissue sections of extrahepatic bile ducts from patients with BA and controls (choledochal cysts and nonbiliary diseases) showed that the activation of NF-kappa B, interferon regulatory factor-3 (IRF-3), and PKR, and the enhancement of TRAIL and single-stranded DNA (ssDNA)-positive apoptosis were significant in BA, although extrahepatic bile ducts diffusely and constantly expressed TLR3 in all diseases. Conclusion: dsRNA viruses could directly induce the expression of TRAIL and apoptosis in human biliary epithelial cells as a result of the biliary innate immune response, supporting the notion that Reoviridae infections are directly associated with the pathogenesis of cholangiopathies in cases of BA.