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.
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