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

胆管上皮细胞具有天然免疫系统的基本成分，包括识别病原体相关分子模式(如脂多糖)的Toll样受体(TLRs)。已知脂多糖可引起细胞损伤，包括细胞凋亡。我们建立了人肝内胆管上皮细胞(HIBECs)，并检测了PAMPS对HIBECs的诱导凋亡作用。细菌PAMPs未发现明显的诱导HIBECs凋亡的作用，但在抑制NFkB依赖的蛋白质合成的情况下，PAMPs以caspase依赖的方式诱导HIBECs的凋亡。相反，用多聚肌苷多胞苷(Poly(I：C)，一种病毒双链RNA的合成类似物)刺激HIBEC，可诱导转录因子(NF-KB和干扰素调节因子3)的激活和干扰素-β1(干扰素-β1)的产生，作为有效的抗病毒反应。此外，Poly(I：C)上调肿瘤坏死因子相关的凋亡诱导配体(TRAIL)的表达，Poly(I：C)和TRAIL通过促进细胞凋亡而降低培养的人HIBEC的存活率。总之，细菌和病毒PAMPs可通过胆道先天免疫反应诱导人胆管上皮细胞的凋亡，支持胆道先天免疫与胆道疾病(如原发性胆汁性肝硬变)的发病机制直接相关的观点。

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