Mechanisms of Alcoholic Liver Disease

酒精性肝病的机制

• 批准号: 7963847
• 负责人: bin gao
• 金额: $ 64.96万
• 依托单位: NATIONAL INSTITUTE ON ALCOHOL ABUSE AND ALCOHOLISM
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7963847
• 关键词: Acceleration; Alcoholic Fatty Liver; Alcoholic Liver Diseases; Alcohols; Apoptosis; Attenuated; Cell Cycle Arrest; Cells; Cytokine Inducible SH2-Containing Protein; Endocannabinoids; Endothelial Cells; Ethanol; Fatty Liver; Fibrosis; Goals; Hepatitis; Hepatocyte; Human; Immunohistochemistry; In Vitro; Inflammation; Inflammatory; Injury; Interferon Type II; Interleukin-10; Interleukin-6; Knockout Mice; Laboratories; Ligands; Liver; Liver Fibrosis; Liver diseases; Mediating; Modeling; Molecular; Mus; Myelogenous; NK Cell Activation; National Institute on Alcohol Abuse and Alcoholism; Natural Killer Cells; Oxidative Stress; Patients; Play; Poly I-C; Production; Resistance; Role; STAT1 protein; Signal Transduction; Signaling Protein; Stat3 protein; System; T-Lymphocyte; Tumor Necrosis Factor-alpha; Tumor Necrosis Factors; Viral hepatitis; Wild Type Mouse; bile duct; cell killing; chronic alcohol ingestion; cytotoxicity; feeding; human TGFB1 protein; liver transplantation; macrophage; member; neutralizing antibody; neutrophil; non-alcoholic fatty liver; novel; prevent; problem drinker; therapeutic target

Our laboratory has been actively studying the molecular mechanisms of alcoholic liver disease, focusing on (1) the role of interleukin-6 (IL-6) and IL-10 and their downstream signal STAT3 in alcoholic fatty liver and liver inflammation; (2) the role of natural killer (NK) cells in alcoholic liver fibrosis. IL-6/IL-10/STAT3 in alcoholic liver disease We have previously demonstrated that IL-6 plays an important role in protecting against liver injury in several murine models of alcoholic liver injury, nonalcoholic fatty liver disease, fatty liver transplantation, and T cell hepatitis. It is believed that the action of IL-6 is mediated via activation of signal transducer and activator of transcription 3 (STAT3). Immunohistochemistry analyses show that phosphorylated STAT3 (STAT3 activation) are detected in hepatocytes, sinusoidal endothelial cells, bile duct-like cells, and inflammatory cells (macrophages, neutrophils etc) in human alcoholic cirrhotic livers. By using liver-specific and macrophage/neutrophil-specific STAT3 knockout mice, we have demonstrated that hepatocyte STAT3 inhibits alcoholic fatty liver but promotes liver inflammation, while myeloid STAT3 inhibits alcoholic liver inflammation. Interestingly, IL-6-deficient mice are more susceptible to alcohol-induced fatty liver and liver injury (hepatocyte apoptosis), while hepatocyte-specific STAT3 knock out mice are only more susceptible to alcohol-induced hepatic steatosis and have similar hepatocyte apoptosis after alcohol feeding compared to wild type mice. This suggests that the hepatoprotection of IL-6 in alcoholic liver injury may be mediated via activation of STAT3-independent signals in hepatocytes, activation of STAT3 in nonparenchymal cells, or both. Our recent studies suggest that endothelial cell STAT3 plays an important role in preventing alcohol-induced liver injury and inflammation. Compared to wild type mice, endothelial cell specific STAT3 knock out mice are more susceptible to alcohol-induced liver inflammation, hepatocyte and endothelial cell apoptosis. Currently, we are also exploring the role of IL-10 in alcoholic liver disease. Abrogation of the anti-fibrotic effect of NK/IFN-gamma contributes to ethanol acceleration of liver fibrosis Chronic alcohol drinking accelerates liver fibrosis in patients with viral hepatitis that cannot be fully explained by ethanol-enhanced liver damage. Recently, 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). 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. In conclusion: 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. In addition, we are also collaborating with Drs. George Kunos and Pal Pacher from NIAAA to investigate the role of the endocannabinoid system in alcoholic liver disease.

本实验室一直在积极研究酒精性肝病的分子机制，重点研究（1）白细胞介素-6（IL-6）和IL-10及其下游信号STAT 3在酒精性脂肪肝和肝脏炎症中的作用;（2）自然杀伤（NK）细胞在酒精性肝纤维化中的作用。 IL-6/IL-10/STAT 3在酒精性肝病中的作用 我们以前已经证明，IL-6在酒精性肝损伤，非酒精性脂肪性肝病，脂肪肝移植和T细胞肝炎的几种小鼠模型中对肝损伤起着重要的保护作用。据信IL-6的作用是通过激活信号转导子和转录激活子3（STAT 3）介导的。免疫组织化学分析表明，磷酸化的STAT 3（STAT 3激活）中检测到肝细胞，窦内皮细胞，胆管样细胞，和炎症细胞（巨噬细胞，中性粒细胞等）在人类酒精性肝硬化。通过使用肝脏特异性和巨噬细胞/嗜中性粒细胞特异性STAT 3敲除小鼠，我们已经证明肝细胞STAT 3抑制酒精性脂肪肝，但促进肝脏炎症，而骨髓STAT 3抑制酒精性肝脏炎症。 有趣的是，IL-6缺陷型小鼠对酒精诱导的脂肪肝和肝损伤（肝细胞凋亡）更敏感，而肝细胞特异性STAT 3敲除小鼠仅对酒精诱导的肝脂肪变性更敏感，并且与野生型小鼠相比，在酒精喂养后具有相似的肝细胞凋亡。这表明IL-6在酒精性肝损伤中的肝保护作用可能通过激活肝细胞中的STAT 3非依赖性信号、激活非实质细胞中的STAT 3或两者来介导。我们最近的研究表明，内皮细胞STAT 3在预防酒精诱导的肝损伤和炎症中起着重要作用。与野生型小鼠相比，内皮细胞特异性STAT 3基因敲除小鼠更容易发生酒精诱导的肝脏炎症、肝细胞和内皮细胞凋亡。 目前，我们还在探索IL-10在酒精性肝病中的作用。 消除NK/IFN-γ的抗纤维化作用有助于乙醇加速肝纤维化 慢性饮酒加速病毒性肝炎患者的肝纤维化，这不能完全解释乙醇增强的肝损伤。最近，我们发现了一种酒精加速肝纤维化的新机制：抑制自然杀伤（NK）细胞和干扰素-γ（IFN-γ）的抗纤维化作用。 与成对喂养的小鼠相比，CCl（4）处理在乙醇喂养的小鼠中诱导了更大的纤维化和更少的HSC凋亡。聚肌胞苷酸（Poly I：C）或IFN-γ治疗抑制了成对喂养的小鼠的肝纤维化，但在乙醇喂养的小鼠中没有。与配对喂养的小鼠相比，在乙醇喂养的小鼠中，Poly I：C激活的NK细胞对HSC的细胞毒性减弱，这是由于自然杀伤细胞2组成员D（NKG 2D）、肿瘤坏死因子相关凋亡诱导配体和乙醇喂养小鼠NK细胞上IFN-γ表达减少。在体外，与成对喂养的小鼠相比，来自乙醇喂养的小鼠的HSC对IFN-γ诱导的细胞周期停滞和凋亡具有抗性。这种抗性是由于来自乙醇喂养小鼠的HSC中的信号转导子和转录激活子1（STAT 1）的IFN-γ激活减少，这是由细胞因子信号传导蛋白的抑制子的诱导和氧化应激的产生引起的。最后，来自乙醇喂养小鼠的HSC对NK细胞杀伤具有抗性，这可以通过转化生长因子β 1（TGF-β 1）中和抗体逆转。最后总结：慢性乙醇消耗减弱了肝脏中NK/IFN-γ/STAT 1的抗纤维化作用，代表了治疗酒精性肝纤维化的新的和不同的治疗靶点。 此外，我们还与来自NIAAA的乔治库诺斯和帕切尔博士合作，研究内源性大麻素系统在酒精性肝病中的作用。