Periductal interleukin-17 production in association with biliary innate immunity contributes to the pathogenesis of cholangiopathy in primary biliary cirrhosis
Periductal interleukin-17 production in association with biliary innate immunity contributes to the pathogenesis of cholangiopathy in primary biliary cirrhosis
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DOI：
10.1111/j.1365-2249.2009.03947.x
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发表时间：
2009-08-01
影响因子：
4.6
通讯作者：
Nakanuma, Y.
中科院分区：
文献类型：
--
作者：
Harada, K.;Shimoda, S.;Nakanuma, Y.
原发性胆汁性肝硬化（PBC）的发病机制可能与对细菌成分的先天免疫反应有关。近年来，以分泌白细胞介素（IL）-17为特征的CD 4阳性辅助性T细胞17（Th 17）与自身免疫性疾病的发病机制有关。人Th 17细胞通过IL-6和IL-1 β从Th 0细胞产生，并通过IL-23维持。在这项研究中，IL-17在PBC中的作用及其与胆道先天免疫的关系进行了研究。使用培养的人胆管上皮细胞（BEC），检测了Th 17相关细胞因子和趋化因子的表达及其在用病原体相关分子模式（PAMP）和IL-17处理时的变化。使用人肝组织样品进行IL-17和Th 17相关细胞因子的免疫组织化学。因此，在BEC中发现了IL-6、IL-1 β、IL-23 p19和IL-23/IL-12 p40 mRNA的表达，以及PAMPs对其的上调。此外，BEC具有IL-17受体，并且用IL-17刺激诱导IL-6、IL-1 β、IL-23 p19和趋化因子的产生。PBC患者胆管中IL-6、IL-1 β表达增强，IL-17阳性细胞浸润。总之，IL-17阳性细胞与PBC中胆管的慢性炎症相关，而慢性炎症与胆汁对PAMPs的先天性免疫反应有因果关系。
An innate immune response to bacterial components is speculated to be involved in the pathogenesis of primary biliary cirrhosis (PBC). Recently, CD4-positive T helper type 17 (Th17) cells, characterized by the secretion of interleukin (IL)-17, have been implicated in the pathogenesis of autoimmune diseases. Human Th17 cells are generated from Th0 cells by IL-6 and IL-1 beta and maintained by IL-23. In this study, the role of IL-17 in PBC and its association with biliary innate immunity were examined. Using cultured human biliary epithelial cells (BECs), the expression of Th17-related cytokines and chemokines and changes therein on treatment with pathogen-associated molecular patterns (PAMPs) and IL-17 were examined. Immunohistochemistry for IL-17 and Th17-related cytokines was performed using tissue samples of human liver. Consequently, the expression of IL-6, IL-1 beta, IL-23p19 and IL-23/IL-12p40 mRNAs, and their up-regulation by PAMPs, were found in BECs. Moreover, BECs possessed IL-17-receptors and stimulation with IL-17 induced production of IL-6, IL-1 beta, IL-23p19 and chemokines. Several IL-17-positive cells had infiltrated damaged bile ducts and the expression of IL-6 and IL-1 beta was enhanced in the bile ducts of PBC patients. In conclusion, IL-17-positive cells are associated with the chronic inflammation of bile ducts in PBC which is associated causally with the biliary innate immune responses to PAMPs.