Biological Significance and Therapeutic Potential of Cyt

细胞因子，包括白细胞介素、生长因子、干扰素和趋化因子，是由肝脏中的多种细胞类型产生的细胞通讯的低分子量介质，包括枯否细胞、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种细胞内信号传导途径介导的，包括Janus激酶-信号转导和转录因子（JAK-STAT）、核因子-κ B和促分裂原活化蛋白（MAP）激酶。多种细胞因子在肝脏疾病中升高，然而这些细胞因子在肝脏中的作用仍然不清楚。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，病毒性肝炎和肝再生中的作用，并开发治疗这些肝脏疾病的潜在治疗方法。我们的部分一直专注于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/STAT 1;白细胞介素6/STAT 3。干扰素-α，-γ/STAT 1：干扰素-α治疗是目前唯一成熟的病毒性肝炎治疗方法。然而，潜在的机制尚不清楚，超过60-80%的患者对这种治疗有抵抗力。我们以前已经证明，干扰素-α激活STAT 1和诱导各种抗病毒和抗肿瘤基因在原代人肝细胞和干扰素-α介导的激活STAT 1在肝脏中被抑制酒精，肿瘤坏死因子-α，白细胞介素-10，白细胞介素-1。在今年，我们已经确定了另一个宿主因子，IFN-γ，也参与了对IFN治疗的抵抗。我们证明了IFN-γ抑制IFN-α信号传导并诱导肝脏中STAT 1的表达。STAT 1的过表达减弱了肝细胞中IFN-α的信号传导。此外，在慢性酒精性肝病中，肝脏中IFN-α信号传导组分和抗病毒蛋白的表达降低。我们还证明了干扰素-γ激活STAT 1并诱导肝脏中STAT 1蛋白的表达，这在伴刀豆球蛋白A和LPS/D-半乳糖胺诱导的肝损伤中的肝损伤中起重要作用。在慢性丙型肝炎患者的肝脏中也检测到高水平的STAT 1蛋白表达，暗示干扰素-γ/STAT 1可能在慢性丙型肝炎感染的发病机制中起重要作用。白细胞介素-6/STAT3：白细胞介素-6（IL-6）激活STAT 3在肝再生和保护肝脏免受各种肝毒素诱导的损伤中起重要作用。我们以前已经证明，酒精抑制IL-6激活肝脏中的STAT 3。目前的研究表明：（1）IL-6/STAT 3通过诱导抗凋亡蛋白和抑制促凋亡STAT 1信号抑制刀豆球蛋白A诱导的T细胞介导的肝炎;（2）白细胞介素-6基因的破坏增加了对酒精性肝病的易感性，这可以通过IL-6治疗逆转。IL-6在体外和体内保护肝细胞免受酒精诱导的活性氧（ROS）、线粒体损伤、凋亡和脂肪变性。提示IL-6水平可能与酒精性肝病的易感性有关，IL-6可能成为治疗酒精性肝病的新药物;（3）IL-6通过防止肝窦内皮细胞损伤和改善肝脏微循环，降低脂肪肝移植后的死亡率和肝损伤。脂肪变性肝脏的IL-6预处理可以使这种同种异体移植物可用于临床移植，从而减少尸体肝脏同种异体移植物的供应和需要肝脏替代的患者数量之间目前存在的并且正在继续增加的差距。 我们还证明了IL-4激活STAT 6在COn A诱导的肝损伤中起有害作用，并且IL-22是肝细胞的生长和存活因子。

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.