Immunity, liver injury and repair

先天免疫、肝损伤、纤维化与修复 我们的实验室正在积极研究：1)天然免疫细胞(NK/NKT细胞)和细胞因子干扰素/信号转导和转录激活因子1(STAT1)在肝损伤、纤维化和再生中的作用；2)乙醇对肝脏天然免疫的影响。 无论病因如何，所有形式的慢性肝损伤都会导致肝纤维化，并伴有细胞外基质蛋白的过度积聚，包括胶原。最近的证据表明，肝纤维化，甚至是肝硬变，是可以逆转的。虽然已知肝星状细胞的激活在肝纤维化的发生发展中起核心作用，但通过细胞凋亡清除肝星状细胞是逆转肝纤维化的关键步骤。然而，在肝纤维化过程中导致肝星状细胞凋亡的因素在很大程度上仍不清楚。我们最近的研究结果表明，NK细胞在肝纤维化过程中在诱导肝星状细胞凋亡中起重要作用。利用体外培养模型，我们证明了NK细胞可以杀死早期激活的肝星状细胞，但不能杀死静止或长期激活的星状细胞。此外，这似乎是由于这样一个事实，即早期激活的肝星状细胞，而不是静止或长期激活的星状细胞，表达高水平的NK细胞激活配体，维甲酸早期诱导基因1(RAe1)，激活NK细胞杀伤。RAE1蛋白最初是从用维甲酸处理的小鼠胚胎癌细胞F9中分离出来的，后来被鉴定为激活NK细胞的NKG2D配体(参见Radaeva等人，2006年)。目前，我们正在探索NKT细胞在慢性肝损伤和肝纤维化中的作用。我们的初步发现表明，NKT细胞在急性肝损伤中发挥不同的作用，但在四氯化碳诱导的慢性肝损伤中，NKT细胞被耗尽，这表明NKT细胞可能在肝纤维化的早期发挥抑制作用，而在疾病的晚期没有抑制作用。 已有文献表明，长期饮酒会加速丙型肝炎病毒感染患者的肝纤维化。人们提出了多种机制来解释乙醇效应的潜在机制。我们的实验室已经证明，长期饮酒会削弱天然免疫细胞(NK/干扰素)的抗纤维化作用，这可能是酒精加速慢性丙型肝炎患者肝纤维化的一个重要机制(见Jeong等人，2008年)。

Innate Immunity, Liver Injury, Fibrosis, and Repair Our laboratory is actively studying: 1) the role of innate immune cells (NK/NKT cells) and cytokines interferon (IFN)/ signal transducer and activator of transcription 1 (STAT1) in liver injury, fibrosis, and regeneration; 2) the effects of ethanol on innate immunity in the liver. Regardless of etiology, all forms of chronic liver injury lead to liver fibrosis accompanied by an excessive accumulation of extracellular matrix proteins, including collagen. Recent evidence suggests that liver fibrosis, and even cirrhosis, can be reversible. While activation of hepatic stellate cells has been known to play a central role in the development and progression of liver fibrosis, the clearance of hepatic stellate cells by apoptosis has been suggested to be a key step involved in reversing liver fibrosis. However, the factors responsible for hepatic stellate cell apoptosis during liver fibrosis remain largely unknown. Our recent findings indicated that NK cells play an important role in inducing hepatic stellate cell apoptosis during liver fibrosis. Using an in vitro culture model, we demonstrated that NK cells kill early-activated hepatic stellate cells, but not quiescent or chronically activated stellate cells. Furthermore, this appeared to be due to the fact that early-activated hepatic stellate cells, but not quiescent or chronically-activated stellate cells, express high levels of the NK cell activating ligand, retinoic acid early inducible gene 1 (RAE1), which activates NK cell killing. RAE1 proteins were originally isolated from mouse embryonic carcinoma F9 cells treated with retinoic acid and later identified as the NKG2D ligand to activate NK cells (see Radaeva et al., 2006). Currently, we are exploring the roles of NKT cells in chronic liver injury and liver fibrosis. Our preliminary findings show that NKT cells play a diverse role in acute liver injury, but are depleted in chronic liver injury induced by carbon tetrachloride, suggesting that NKT cells may play a role in inhibiting the early stage of liver fibrosis but not the late stage of disease. It is well documented that chronic alcohol consumption accelerates liver fibrosis in patients with hepatitis C virus (HCV) infection. Multiple mechanisms have been proposed to explain the underlying mechanisms mediating ethanols effects. Our laboratory has demonstrated that chronic alcohol consumption attenuates the anti-fibrotic effects of innate immune cells (NK/IFN-), which could be an important mechanism contributing to alcohol acceleration of liver fibrosis in patients with chronic HCV infection (see Jeong et al., 2008).