Jeong Won-Il, Park Ogyi, Gao Bin
Section on Liver Biology, Laboratory of Physiologic Studies, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland, USA.
Gastroenterology. 2008 Jan;134(1):248-58. doi: 10.1053/j.gastro.2007.09.034. Epub 2007 Sep 29.
BACKGROUND & AIMS: Chronic alcohol drinking accelerates liver fibrosis in patients with viral hepatitis that cannot be fully explained by ethanol-enhanced liver damage. Here, we identified a novel mechanism by which alcohol accelerates liver fibrosis: inhibition of the antifibrotic effects of natural killer (NK) cells and interferon-gamma (IFN-gamma).
Alcohol administration was achieved by feeding mice with a liquid diet containing 5% ethanol for 8 weeks. Liver fibrosis was induced by administration of carbon tetrachloride (CCl(4)) for 2 weeks. Hepatic stellate cells (HSCs) were also isolated and cultured for in vitro studies.
CCl(4) treatment induced greater fibrosis and less apoptosis of HSCs in ethanol-fed mice compared with pair-fed mice. Polyinosinic-polycytidylic acid (Poly I:C) or IFN-gamma treatment inhibited liver fibrosis in pair-fed but not in ethanol-fed mice. Poly I:C activation of NK cell cytotoxicity against HSCs was attenuated in ethanol-fed mice compared with pair-fed mice, which was due to reduced natural killer group 2 member D (NKG2D), tumor necrosis factor-related apoptosis-inducing ligand, and IFN-gamma expression on NK cells from ethanol-fed mice. In vitro, HSCs from ethanol-fed mice were resistant to IFN-gamma-induced cell cycle arrest and apoptosis compared with pair-fed mice. Such resistance was due to diminished IFN-gamma activation of signal transducer and activator of transcription 1 (STAT1) in HSCs from ethanol-fed mice caused by the induction of suppressors of cytokine signaling proteins and the production of oxidative stress. Finally, HSCs from ethanol-fed mice were resistant to NK cell killing, which can be reversed by transforming growth factor-beta1 (TGF-beta1) neutralizing antibody.
Chronic ethanol consumption attenuates the antifibrotic effects of NK/IFN-gamma/STAT1 in the liver, representing new and different therapeutic targets with which to treat alcoholic liver fibrosis.
长期饮酒会加速病毒性肝炎患者的肝纤维化，而乙醇所致肝损伤并不能完全解释这一现象。在此，我们发现了酒精加速肝纤维化的一种新机制：抑制自然杀伤（NK）细胞和干扰素-γ（IFN-γ）的抗纤维化作用。
通过给小鼠喂食含5%乙醇的液体饲料8周来实现酒精摄入。通过给予四氯化碳（CCl₄）2周诱导肝纤维化。还分离并培养肝星状细胞（HSCs）用于体外研究。
与配对喂养的小鼠相比，CCl₄处理在乙醇喂养的小鼠中诱导了更严重的纤维化和更少的HSCs凋亡。聚肌苷酸-聚胞苷酸（Poly I:C）或IFN-γ处理可抑制配对喂养小鼠的肝纤维化，但对乙醇喂养小鼠无效。与配对喂养的小鼠相比，乙醇喂养小鼠中Poly I:C激活的NK细胞对HSCs的细胞毒性减弱，这是由于乙醇喂养小鼠的NK细胞上自然杀伤细胞2型成员D（NKG2D）、肿瘤坏死因子相关凋亡诱导配体和IFN-γ表达降低。在体外，与配对喂养的小鼠相比，乙醇喂养小鼠的HSCs对IFN-γ诱导的细胞周期阻滞和凋亡具有抗性。这种抗性是由于细胞因子信号蛋白抑制因子的诱导和氧化应激的产生导致乙醇喂养小鼠的HSCs中IFN-γ激活的信号转导和转录激活因子1（STAT1）减少。最后，乙醇喂养小鼠的HSCs对NK细胞杀伤具有抗性，转化生长因子-β1（TGF-β1）中和抗体可逆转这种抗性。
长期乙醇摄入减弱了肝脏中NK/IFN-γ/STAT1的抗纤维化作用，这代表了治疗酒精性肝纤维化的新的且不同的治疗靶点。
