Department of Gastroenterology, Juntendo University School of Medicine, Tokyo, Japan.
J Hepatol. 2011 Jun;54(6):1195-204. doi: 10.1016/j.jhep.2010.08.022. Epub 2010 Nov 5.
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.
Male CD1d-knockout (KO) and wild-type (WT) mice were given repeated intraperitoneal injections of thioacetamide (TAA, 3times/week; 0.1-0.2mg/g BW) for up to 9 weeks, or a single intraperitoneal injection of CCl(4) (1 μl/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).
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 α-actin (SMA) and transforming growth factor (TGF)β1 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 α1(I)procollagen (COL1A1) and tissue inhibitor of matrix metalloproteinase (TIMP)-1 mRNA were blunted significantly in CD1d-KO mice. Similarly, acute CCl(4)-induced hepatic injury and subsequent profibrogenic responses were also reduced significantly in CD1d-KO mice.
These findings clearly indicated that CD1d-restricted NKT cells contribute to xenobiotics-induced hepatic inflammation, hepatocellular damage, and subsequent profibrogenic responses in the liver.
有几条证据表明先天免疫在肝纤维化中起着关键作用。为了阐明自然杀伤 (NK) T 细胞在肝炎症和纤维化中的作用，我们在此研究了因 CD1d 分子基因缺失导致成熟 NKT 细胞缺失的小鼠中外源物诱导的肝损伤和随后的纤维化。
雄性 CD1d 敲除 (KO) 和野生型 (WT) 小鼠接受硫代乙酰胺 (TAA，每周 3 次；0.1-0.2mg/g BW) 重复腹腔内注射，最多 9 周，或单次腹腔内注射 CCl(4)（1μl/g）。评估肝组织学，并通过实时逆转录聚合酶链反应 (RT-PCR) 定量测量肝内细胞因子和基质相关基因的表达水平。
TAA 重复注射后 KO 小鼠的死亡率几乎完全得到预防。TAA 诱导的炎症反应和肝细胞损伤在 KO 小鼠中明显改善。TAA 诱导的肝内平滑肌 α-肌动蛋白 (SMA) 和转化生长因子 (TGF)β1 mRNA 的表达也在 KO 小鼠中得到了很大程度的预防。事实上，在 TAA 给药 9 周后，KO 小鼠仅发展出最小的肝纤维化，而 WT 小鼠则出现明显的桥接纤维化。事实上，TAA 诱导的 α1(I)前胶原 (COL1A1) 和基质金属蛋白酶组织抑制剂 (TIMP)-1 mRNA 的增加在 KO 小鼠中明显减弱。同样，CD1d-KO 小鼠中 CCl(4)诱导的急性肝损伤和随后的促纤维化反应也显著减少。
这些发现清楚地表明，CD1d 限制性 NKT 细胞有助于外源性物质诱导的肝炎症、肝细胞损伤和随后的肝纤维化反应。
