Monocyte chemoattractant protein-1 derived from biliary innate immunity contributes to hepatic fibrogenesis
Monocyte chemoattractant protein-1 derived from biliary innate immunity contributes to hepatic fibrogenesis
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DOI：
10.1136/jclinpath-2011-200040
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发表时间：
2011-04
影响因子：
3.4
通讯作者：
K. Harada;M. Chiba;A. Okamura;Maylee Hsu;Yasunori Sato;Saya Igarashi;X. Ren;H. Ikeda;H. Ohta;S. Kasashima;A. Kawashima;Y. Nakanuma
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文献类型：
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作者：
K. Harada;M. Chiba;A. Okamura;Maylee Hsu;Yasunori Sato;Saya Igarashi;X. Ren;H. Ikeda;H. Ohta;S. Kasashima;A. Kawashima;Y. Nakanuma
目的单核细胞趋化蛋白-1(MCP-1)是与肝纤维化相关的肝星状细胞(HSCs)的主要趋化因子。本研究发现，在来源于胆管上皮细胞(BECs)的多种纤维化因子中，胆道天然免疫系统产生的单核细胞趋化蛋白-1(MCP-1)在肝纤维化的组织发生中起着最关键的作用。方法采用体外培养的人脐静脉内皮细胞，观察Toll样受体配体、炎性细胞因子、胆汁酸刺激下MCP-1等5种促纤维化因子的表达。此外，用免疫组织化学方法对正常肝和病变肝组织中的单核细胞趋化蛋白-1和α-平滑肌肌动蛋白进行了原位检测。结果Toll样受体配体、IL-1β和肿瘤坏死因子-α均可上调BEC中纤维化因子的表达，但仅MCP-1表达上调。α-平滑肌肌动蛋白阳性活化的肝星状细胞在病变肝组织中可见界面区增殖胆管表达单核细胞趋化蛋白-1。结论胆小管在多种肝胆疾病中均有增殖，其意义尚不清楚。本研究证实胆管内的BECs可产生MCP-1，尤其是通过胆道天然免疫，提示BECs来源的MCP-1在HSCs向界面区募集和激活HSCs导致门静脉周围纤维化的进展中起重要作用。
Aims Monocyte chemoattractant protein-1 (MCP-1) is a major chemotactic factor for hepatic stellate cells (HSCs) associated with hepatic fibrosis. In this study, among several fibrogenetic factors derived from biliary epithelial cells (BECs), MCP-1 produced by the biliary innate immune system was found to be most critical in the histogenesis of hepatic fibrogenesis. Methods Using cultured human BECs, the expression of five fibrogenetic factors including MCP-1 on stimulation with Toll-like receptor ligands, inflammatory cytokines or bile acids was examined. Moreover, in situ detection of MCP-1 and α-smooth muscle actin proteins was performed using sections from normal and diseased livers by immunohistochemistry. Results All fibrogenetic factors were detected in BECs, but only MCP-1 expression was upregulated, by all the Toll-like receptor ligands, IL-1β, and tumour necrosis factor-alpha. Proliferating bile ductules in interface areas expressed MCP-1 in diseased livers accompanying α-smooth muscle actin-positive activated HSCs. Conclusions Bile ductules proliferate in various hepatobiliary diseases, and its significance is still unknown. This study demonstrated that BECs in bile ductules could produce MCP-1, particularly, via biliary innate immunity, suggesting that MCP-1 derived from BECs plays an important role in the recruitment of HSCs to interface areas and the activation of HSCs resulting in the progression of periportal fibrosis.