Accelerated Liver Fibrosis in Hepatitis B Virus Transgenic Mice: Involvement of Natural Killer T Cells
Accelerated Liver Fibrosis in Hepatitis B Virus Transgenic Mice: Involvement of Natural Killer T Cells
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乙型肝炎病毒转基因小鼠加速肝纤维化：自然杀伤 T 细胞的参与
DOI：
10.1002/hep.23983
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发表时间：
2011-01-01
期刊：
影响因子：
13.5
通讯作者：
Tian, Zhigang
中科院分区：
文献类型：
--
作者：
Jin, Zixue;Sun, Rui;Tian, Zhigang
从B型肝炎病毒（HBV）感染到肝纤维化的免疫病理过程由于缺乏动物模型而不完全清楚。本研究通过观察HBV转基因小鼠（HBV-tg）肝纤维化的发生发展，探讨自然杀伤T细胞（NKT）在HBV相关肝纤维化中的作用。我们发现HBV-tg小鼠肝纤维化自发发展，colla 1，基质金属蛋白酶（MMP）2和金属蛋白酶组织抑制剂（TIMP）1的转录升高。然后给小鼠重复注射肝毒素四氯化碳（CCl 4）以诱导显著的肝纤维化。慢性CCl 4处理后，HBV-tg小鼠血清丙氨酸氨基转移酶（ALT）升高，肝再生结节增多、变大，肝纤维化面积明显增加。此外，CCl 4处理的HBV-tg小鼠肝脏中colla 1和MMP 2转录的增加更大，TIMP 1的水平持续高，肝星状细胞（HSC）的活化更大。实验结果还表明，注射CCl_4后，HBV-tg小鼠肝脏单个核细胞（MNCs）增多，过继转移的HBV-tg小鼠淋巴细胞在Rag 1（-/-）小鼠肝脏胶原沉积增加。进一步的研究表明，长期CCl 4处理后，HBV-tg小鼠肝脏NKT细胞数量增加，NKT细胞过度活化。通过去除HBV-tg小鼠的NKT细胞并将纯化的NKT细胞从HBV-tg小鼠过继转移到受体Ragl（-/-）小鼠中，进一步证实了NKT细胞对于HSC活化是关键的。在体外共培养实验中，NKT细胞产生的炎性细胞因子IL-4和IL-13在HSC活化中起关键作用。结论：HBV-tg小鼠的NKT细胞在肝纤维化过程中可诱导HSC活化。（肝脏学2011;53：219-229）
The immunopathogenic process from hepatitis B virus (HBV) infection to liver fibrosis is incompletely understood because it lacks an animal model. In this study we observed the development of liver fibrosis in HBV transgenic (HBV-tg) mice and found the roles of natural killer T (NKT) cells in HBV-related liver fibrosis. We found liver fibrosis spontaneously developed in HBV-tg mice with the elevated transcription of colla1, matrix metalloproteinase (MMP)2, and tissue inhibitor of metalloproteinase (TIMP) 1. Mice were then injected with repetitive hepatotoxin carbon tetrachloride (CCl4) to induce prominent liver fibrosis. After chronic CCl4 treatment, the serum alanine aminotransferase (ALT) was higher, the liver regenerative nodules became more and bigger, and the fibrosis area was remarkably increased in HBV-tg mice than in C57BL/6 mice. Moreover, the increase in colla1 and MMP2 transcription was greater, with a sustaining high level of TIMP1 and a greater activation of hepatic stellate cells (HSCs) in the livers of CCl4-treated HBV-tg mice. Our data also showed that there were more liver mononuclear cells (MNCs) in HBV-tg mice after CCl4 injection, and Rag1(-/-) mice adoptive transferred lymphocytes from HBV-tg mice displayed increased collagen deposition. Further study demonstrated the number of liver NKT cells increased after CCl4 treatment and NKT cells were overactivated in HBV-tg mice in the long term. It was further confirmed that NKT cells were critical for HSCs activation by depletion of NKT cells of HBV-tg mice and adoptive transfer of purified NKT cells from HBV-tg mice into recipient Ragl(-/-) mice. The inflammatory cytokines IL-4 and IL-13 produced by NKT cells played a pivotal role in HSCs activation in an in vitro coculture experiment. Conclusion: These data suggest that NKT cells from HBV-tg mice induce the HSCs activation in liver fibrogenesis. (HEPATOLOGY 2011;53:219-229)