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

胆管上皮细胞拥有由 Toll 样受体 (TLR) 组成的先天免疫系统的重要组成部分，该受体可识别脂多糖 (LPS) 等病原体相关分子模式 (PAMP)，已知会导致细胞损伤，包括细胞凋亡。人肝内胆管上皮细胞（HIBEC）并检查了 PAMP 诱导的 HIBEC 细胞凋亡，但用 10 毫克/升的处理未发现明显的细胞凋亡诱导。任何细菌 PAMP，但在抑制 NF-KB 依赖性蛋白质合成的情况下，HIBEC 以半胱天冬酶依赖性方式通过 PAMP 发生凋亡，相反，用聚肌苷-聚胞苷酸 (poly(I:C)、病毒 dsRNA 的合成类似物）诱导转录因子（NF-KB 和干扰素调节因子 3）的激活以及干扰素-β1 (IFN-β1) 的产生此外，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 均通过降低培养的人 HIBEC 的活力。总之，由于胆道先天免疫反应，细菌和病毒 PAMP 可以诱导人胆道上皮细胞凋亡，这支持了胆道先天免疫与胆道先天免疫直接相关的观点。原发性胆汁性肝硬化等胆道疾病中胆管病的发病机制