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Innate Immune Response Induces Apoptosis and Regulates Apoptosis-related Molecules in Human Biliary Epithelial Cells

先天免疫反应诱导细胞凋亡并调节人胆管上皮细胞中的细胞凋亡相关分子

基本信息

批准号：
18590326
负责人：
HARADA Kenichi
金额：
$ 2.43万
依托单位：
Kanazawa University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2006
资助国家：
日本
起止时间：
2006 至 2007
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-18590326/
关键词：
cholangiocytes apoptosis innate immunity TLR primary biliary cirrhosis biliary atresia PAMPs double-stranded RNA Fas caspase NF-κB

项目摘要

Biliary epithelial cells possess the essential components of the innate immune system consisting of Toll-like receptors (TLRs) which recognize pathogen-associated molecular patterns (PAMPs) such as lipopolysaccharide (LPS). LPS is known to cause cell injury including apoptosis. We established human intrahepatic biliary epithelial cells (HIBECs) and examined the PAMPs-induced apoptosis in HIBECs. The distinct induction of apoptosis was not found by the treatment with any bacterial PAMPs, but in the condition of an inhibition of NF-KB-dependent protein synthesis, HIBECs undergo apoptosis by PAMPs in the manner of caspase-dependence. In contrast, stimulation with polyinosinic-polycytidylic acid (poly(I:C), a synthetic analog of viral dsRNA) induced the activation of transcription factors (NF-KB and interferon regulatory factor 3) and the production of interferon-β1 (IFN-β1) as potent antiviral responses in HIBECs. 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 HIBECs by enhancing apoptosis. In conclusion, bacterial and viral PAMPs could induce the apoptosis in human biliary epithelial cells as a result of the biliary innate immune response, supporting the notion that biliary innate immunity is directly associated with the pathogenesis of cholangiopathies in biliary diseases such as primary biliary cirrhosis

胆管上皮细胞具有先天免疫系统的基本组分，其由Toll样受体（TLR）组成，所述TLR识别病原体相关分子模式（PAMP），例如脂多糖（LPS）。已知LPS引起细胞损伤，包括细胞凋亡。我们建立了人肝内胆管上皮细胞（HIBECs），并研究了PAMPs诱导的HIBECs凋亡。任何细菌PAMPs处理均未发现明显的凋亡诱导作用，但在抑制NF-κ B依赖的蛋白质合成的条件下，PAMPs以caspase依赖的方式诱导HIBEC凋亡。相反，用多聚肌苷酸-多聚胞苷酸（poly（I：C），病毒dsRNA的合成类似物）刺激诱导转录因子（NF-κ B和干扰素调节因子3）的活化和干扰素-β1（IFN-β1）的产生，作为HIBEC中的有效抗病毒应答。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HIBECs的活力。结论：细菌和病毒PAMPs可诱导人胆管上皮细胞凋亡，这是胆汁天然免疫应答的结果，支持胆汁天然免疫与原发性胆汁性肝硬化等胆道疾病的发病机制直接相关的观点