CD1d-restricted natural killer T cells contribute to hepatic inflammation and fibrogenesis in mice
CD1d-restricted natural killer T cells contribute to hepatic inflammation and fibrogenesis in mice
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DOI：
10.1016/j.jhep.2010.08.022
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发表时间：
2011-06-01
影响因子：
25.7
通讯作者：
Watanabe, Sumio
中科院分区：
文献类型：
--
作者：
Ishikawa, Sachiko;Ikejima, Kenichi;Watanabe, Sumio
背景与目的：多项证据表明先天免疫在肝纤维化中起关键作用。为了阐明自然杀伤(NK)T细胞在肝脏炎症和纤维化形成中的作用，我们研究了CD1d分子基因突变导致成熟NKT细胞缺失的外源生物诱导的肝损伤和随后的纤维化形成。方法：雄性CD1d基因敲除(KO)和野生型(WT)小鼠重复给予硫代乙酰胺(TAA)，每周3次，0.1-0.2 mg/gbw，持续9周，或一次性给予CCl4(1 MU L/g)。采用实时定量逆转录聚合酶链式反应(RT-PCR)检测肝组织中细胞因子和基质相关基因的表达水平。结果：CD1d-KO小鼠多次注射TAA后死亡几乎完全避免。CD1d-KO小鼠TAA诱导的炎症反应和肝细胞损伤明显减轻。在CD1d-KO小鼠中，TAA诱导的肝脏平滑肌α-肌动蛋白(SMA)和转化生长因子(TGF)β1mRNA的表达也被很大程度地阻止。事实上，CD1d-KO小鼠在服用TAA 9周后出现了轻微的肝纤维化，这导致了WT小鼠明显的桥接纤维化。事实上，在CD1d-KO小鼠中，TAA诱导的α1(L)前胶原(COL1A1)和基质金属蛋白酶组织抑制因子(TIMP)-1mRNA的增加显著减弱。同样，CD1d-KO小鼠的急性CCl4诱导的肝损伤和随后的促纤维化反应也显著减少。结论：这些发现清楚地表明CD1d限制的NKT细胞参与了异物诱导的肝脏炎症、肝细胞损伤和随后的肝脏促纤维化反应。(C)2010年欧洲肝脏研究协会。爱思唯尔出版，版权所有。
Background & Aims: Several lines of evidence suggest that innate immunity plays a key role in hepatic fibrogenesis. To clarify the role of natural killer (NK) T cells in hepatic inflammation and fibrogenesis, we here investigated xenobiotics-induced liver injury and subsequent fibrogenesis in mice lacking mature NKT cells caused by genetic disruption of the CD1d molecule.Methods: Male CD1d-knockout (KO) and wild-type (WT) mice were given repeated intraperitoneal injections of thioacetamide (TAA, 3 times/week; 0.1-0.2 mg/g BW) for up to 9 weeks, or a single intraperitoneal injection of CCl4 (1 mu l/g). Liver histology was evaluated, and expression levels of cytokines and matrix-related genes in the liver were quantitatively measured by real-time reverse transcription-polymerase chain reaction (RT-PCR).Results: Mortality following repeated injections of TAA was prevented almost completely in CD1d-KO mice. TAA-induced inflammatory responses and hepatocellular damage were markedly ameliorated in CD1d-KO mice. TAA-induced expression of smooth muscle alpha-actin (SMA) and transforming growth factor (TGF)beta 1 mRNA in the liver were also prevented largely in CD1d-KO mice. In fact, CD1d-KO mice developed minimal hepatic fibrosis after 9-weeks of administration of TAA, which caused overt bridging fibrosis in WT mice. Indeed, TAA-induced increases in alpha 1(l)procollagen (COL1A1) and tissue inhibitor of matrix metalloproteinase (TIMP)-1 mRNA were blunted significantly in CD1d-KO mice. Similarly, acute CCl4-induced hepatic injury and subsequent profibrogenic responses were also reduced significantly in CD1d-KO mice.Conclusions: These findings clearly indicated that CD1d-restricted NKT cells contribute to xenobiotics-induced hepatic inflammation, hepatocellular damage, and subsequent profibrogenic responses in the liver. (C) 2010 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.