Biological Significance and Therapeutic Potential of Cyt

细胞色素的生物学意义和治疗潜力

• 批准号: 6818687
• 负责人: bin gao
• 金额: --
• 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/6818687
• 关键词: alcoholic hepatitis; alcoholism /alcohol abuse; biological signal transduction; cytokine; gene expression; growth factor; hepatotoxin; human tissue; infectious hepatitis; interferon alpha; interferon gamma; interleukin 6; liver cells; liver regeneration; transcription factor

Cytokines, including interleukins, growth factors, interferons and chemokines, are low-molecular-weight mediators of cellular communication produced by multiple cell types in the liver, including Kupffer cell, hepatic lymphocytes, endothelial cells, and stellate cells. The actions of cytokines are mediated through activation of several intracellular signaling pathways, including the Janus kinase-signal transducer and transcription factor (JAK-STAT), nuclear factor-kappa B, and mitogen-activated protein (MAP) kinases. A wide variety of cytokines are elevated in liver disease, however the roles of these cytokines in the liver remain obscure. The Section on Liver Biology is studying the role of cytokines and growth factors in alcoholic liver disease, viral hepatitis, and liver regeneration, and developing potential therapeutic approaches to treat these liver disorders. Our section has been focusing on two major cytokines and their signals in alcoholic liver disease and viral hepatitis: Interferon-alpah,-gamma/STAT1; Interleukin-6/STAT3. Interferon-alpha,-gamma/STAT1: Interferon-alpha treatment is currently the only well-established therapy for viral hepatitis. However, the underlying mechanisms are not clear and more than 60-80% of patients are resistant to such therapy. We have previously demonstrated that interferon-alpha activates STAT1 and induces a variety of antiviral and antitumor genes in primary human hepatocytes and that interferon-alpha-mediated activation of STAT1 in the liver is suppressed by alcohol, tumor necrosis factor-alpha, interlukin-10, and interleukin-1. In this year, we have identified that another host factor, IFN-gamma, is also involved in resistance to IFN therapy. We demonstrate that IFN-gamma suppresses IFN-alpha signaling and induces expression of STAT1 in the liver. Overexpression of STAT1 attenuates IFN-alpha signaling in hepatocytes. Furthermore, expression of IFN-alpha signaling components and antiviral proteins in the liver are decreased in chronic alcoholic liver disease. We have also demonstrated that interferon-gamma activates STAT1 and induces STAT1 protein expression in the liver, which plays an essential role in liver injury in Concanavalin A- and LPS/D-galactosamine-induced liver injury. High levels of STAT1 protein expression are also detected in the liver of patients with chronic hepatitis C infection, implicating that interferon-gamma/STAT1 may play an important role in the pathogenesis of chronic hepatitis C infection. Interleukin-6/STAT3: Interleukin-6 (IL-6) activation of STAT3 plays an important role in liver regeneration and protection of the liver from injury induced by a variety of hepatoxins. We have previously demonstrated that alcohol inhibits IL-6 activation of STAT3 in the liver. Current studies demonstrate (1) that IL-6/STAT3 suppresses Concanavalin A-induced T cell-mediated hepatitis via induction of anti-apoptotic proteins and inhibition of proapoptotic STAT1 signals; (2) that disruption of the interlukin-6 gene increases the susceptibility to alcoholic liver disease, which can be reversed by IL-6 treatment. IL-6 protects against alcohol-induced reactive oxygen species (ROS), mitochondrial injury, apoptosis, and steatosis in hepatocytes in vitro and in vivo. These findings suggest that levels of IL-6 may be associated with the susceptibility to alcoholic liver disease and IL-6 could be a novel therapeutic agent to treat alcoholic liver disease; (3) that IL-6 reduces mortality and liver injury in steatotic liver isografts following transplantation via preventing sinusoidal endothelial cell damage and consequent amelioration of hepatic microcirculation. IL-6 pretreatment of steatotic livers may render such allografts useable for clinical transplantation, thereby decreasing the gap which currently exists and is continuing to increase between the supply of cadaveric liver allografts and the number of patients in need of liver replacement. We have also demonstrated that IL-4 activation of STAT6 plays a deleterious role in COn A-induced liver injury and IL-22 is a growth and survival factor for hepatocytes.

细胞因子，包括白介素类、生长因子、干扰素和趋化因子，是肝脏多种细胞产生的低分子细胞通讯介质，包括库普弗细胞、肝淋巴细胞、内皮细胞和星状细胞。细胞因子的作用是通过激活几条细胞内信号通路来实现的，包括Janus激酶信号转导和转录因子(JAK-STAT)、核因子-kappaB和丝裂原活化蛋白(MAP)激酶。多种细胞因子在肝病中升高，但这些细胞因子在肝脏中的作用尚不清楚。肝脏生物学部分正在研究细胞因子和生长因子在酒精性肝病、病毒性肝炎和肝脏再生中的作用，并开发潜在的治疗方法来治疗这些肝脏疾病。我们的部分主要关注酒精性肝病和病毒性肝炎中的两种主要细胞因子及其信号：干扰素-α、-γ/STAT1和白介素6/STAT3。干扰素-α，-γ/STAT1：干扰素-α疗法是目前唯一公认的治疗病毒性肝炎的方法。然而，其潜在的机制尚不清楚，超过60%-80%的患者对这种疗法具有抵抗力。我们以前已经证明，干扰素-α激活STAT1并在原代人肝细胞中诱导多种抗病毒和抗肿瘤基因，并且干扰素-α介导的肝脏中STAT1的激活可被酒精、肿瘤坏死因子-α、白介素10和白介素1抑制。今年，我们发现了另一种宿主因子，干扰素-γ，也参与了对干扰素治疗的抵抗。我们证明，干扰素-γ抑制干扰素-α信号转导，并诱导肝脏中STAT1的表达。STAT1的过表达减弱了肝细胞中的干扰素-α信号。此外，在慢性酒精性肝病中，肝脏中干扰素-α信号成分和抗病毒蛋白的表达减少。在刀豆蛋白A和脂多糖/D-氨基半乳糖诱导的肝损伤中，干扰素-γ激活STAT1并诱导STAT1蛋白的表达在肝损伤中起重要作用。慢性丙型肝炎患者肝脏中也检测到高水平的STAT1蛋白表达，提示干扰素-γ/STAT1可能在慢性丙型肝炎的发病机制中起重要作用。白介素6/STAT3：白介素6(IL-6)激活STAT3在肝脏再生和保护肝脏免受多种肝毒素损伤中起重要作用。我们先前已经证明，酒精抑制肝脏中STAT3的IL-6激活。目前的研究表明，(1)IL-6/STAT3通过诱导抗凋亡蛋白和抑制促凋亡信号STAT1来抑制刀豆蛋白A诱导的T细胞介导的肝炎；(2)IL-6基因的破坏增加了酒精性肝病的易感性，这可被IL-6治疗逆转。IL-6在体外和体内对酒精诱导的肝细胞的ROS、线粒体损伤、细胞凋亡和脂肪变性具有保护作用。提示IL-6水平可能与酒精性肝病的易感性有关，IL-6有可能成为治疗酒精性肝病的新药物；(3)IL-6通过预防肝窦内皮细胞损伤，改善肝脏微循环，减少脂肪变性肝移植后的死亡率和肝损伤。对脂肪变性的肝脏进行IL-6的预处理可以使这种同种异体肝移植用于临床移植，从而缩小目前存在的并将继续增加的身体肝移植供应与需要肝脏置换的患者数量之间的差距。 我们还证实，IL-4活化的STAT6在ConA诱导的肝损伤中起着有害的作用，而IL-22是肝细胞的生长和生存因子。