Massive liver necrosis after provocation of imbalance between Th1 and Th2 immune reactions in osteopontin transgenic mice
Massive liver necrosis after provocation of imbalance between Th1 and Th2 immune reactions in osteopontin transgenic mice
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DOI：
10.1007/s00535-004-1403-0
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发表时间：
2004-09-01
影响因子：
6.3
通讯作者：
Fujiwara, K
中科院分区：
文献类型：
--
作者：
Mimura, S;Mochida, S;Fujiwara, K
背景肝脏中辅助性T细胞（Th）1和Th 2免疫反应失衡可导致大面积肝坏死。骨桥蛋白是一种分泌的糖蛋白，用于启动Th 1免疫反应，以及用于骨和肾中的细胞外基质形成和钙沉积。骨桥蛋白在枯否细胞、巨噬细胞和受损肝脏中活化的星状细胞中过表达。我们建立了转基因小鼠表达骨桥蛋白只在肝细胞中，使用载体含有人血清淀粉样蛋白P组分启动子。利用这些转基因小鼠研究了Th 1/Th 2免疫失衡与大面积肝坏死的关系。方法.对转基因小鼠和C27 BL/6小鼠（转基因小鼠的野生型对照）静脉注射伴刀豆球蛋白A，并评价肝损伤的组织学程度和血浆细胞因子水平。结果当转基因小鼠接受伴刀豆球蛋白A时，肝脏中出现大量坏死和单核细胞浸润，雌性小鼠的程度大于雄性小鼠。该处理在雄性和雌性C57 BL/6小鼠中产生了极轻微的肝损伤和局灶性肝坏死。在这些转基因小鼠和对照小鼠中，伴刀豆球蛋白A治疗后白细胞介素（IL）-10和干扰素（IFN）-γ的血浆浓度增加。然而，血浆IL-10浓度的上调在雄性和雌性转基因小鼠中比在对照小鼠中小，并且IFN-γ浓度的上调在雌性转基因小鼠中比在雌性对照小鼠中大。结论.伴刀豆球蛋白A治疗后，Th 1和Th 2免疫反应紊乱，在肝细胞中表达骨桥蛋白的转基因小鼠中，Th 1免疫占主导地位;这种免疫失衡可能导致大规模肝坏死。
Background Massive liver necrosis can develop as a consequence of imbalance between T-helper (Th)1 and Th2 immune reactions in the liver. Osteopontin is a glycoprotein secreted for the initiation of the Th1 immune reaction, as well as for extracellular matrix formation and calcium deposition in the bone and kidney. Osteopontin is overexpressed in Kupffer cells, macrophages, and stellate cells activated in injured livers. We established transgenic mice expressing osteopontin exclusively in hepatocytes, using a vector containing human serum amyloid P component promoter. The relation of Th1/Th2 immune imbalance to massive liver necrosis was studied using these transgenic mice. Methods. Transgenic mice and C27BL/6 mice, wild-type controls of the transgenic mice, were given an intravenous injection of concanavalin-A, and the histological extent of liver injuries and plasma cytokine levels were evaluated. Results. When the transgenic mice received concanavalin-A, massive necrosis and mononuclear cell infiltration developed in the liver, the extent of which was greater in the female mice than in the male mice. This treatment produced minimal liver injury and focal liver necrosis in male and female C57BL/6 mice. In these transgenic and control mice, plasma concentrations of interleukin (IL)-10 and interferon (IFN)-gamma were increased after concanavalin-A treatment. However, the upregulation of plasma IL-10 concentration was smaller in the male and female transgenic mice than in the control mice, and the upregulation of the IFN-gamma concentration was greater in the female transgenic mice than in the female control mice. Conclusions. Th1 and Th2 immune reactions were deranged after concanavalin-A treatment, with Th1 immunity predominating in transgenic mice expressing osteopontin in hepatocytes; this immunological imbalance may contribute to massive liver necrosis.