Mechanisms Associated With Interferon-α Treatment of Liver Cirrhosis

• Main Authors: Chih-Ying Lee, 李至瑩
• Other Authors: Lih-Hwa Hwang
• Format: Others
• Language: en_US
• Published: 2010
• Online Access: http://ndltd.ncl.edu.tw/handle/62173095328522782700

碩士 === 國立陽明大學 === 微生物及免疫學研究所 === 98 === Liver cirrhosis represents a significant medical problem worldwide. It is viewed as a wound-healing response to a variety of liver injury, resulting in excessive deposition of extracellular matrix (ECM), which leads to distortion of normal architecture and loss of function of the liver. Among the causes of liver cirrhosis, hepatitis viral infections, alcohol abuse, and nonalcoholic steatohepatitis (NASH) are the major leading ones. Actually, liver cirrhosis is considered to act as the precursor and promoter of hepatocellular carcinoma (HCC). Within 70~80% of patients, the malignant tumors emerge from a background of liver cirrhosis. In our previous study, we have established an animal model in which HCC and liver cirrhosis develop simultaneously by administration of diethylnitrosamine (DEN). Using this model similar to most human HCC, we evaluated the therapeutic effects of adenovirus-mediated interferon-α (IFN-α) gene therapy. Our results revealed that IFN-α treatment not only suppressed tumor growth but also ameliorated liver fibrosis. Thus, IFN-α gene therapy represents a promising strategy to treat HCC and liver cirrhosis. In this study, we further investigated the underlying mechanisms associated with the anti-cirrhotic activity of IFN-α. The hepatic stellate cell (HSC) plays a key role in liver fibrogenesis, serving as the major resource of fibrillar collagen. Proinflammatory cytokines and reactive oxygen species (ROS), produced following liver injury, induce activation of HSCs. Activated stellate cells become proliferative as well as fibrogenic, and produce massive amounts of type I collagen. Therefore, we focused on the impacts of IFN-α on these activated HSCs in this study. Our results demonstrated that IFN-α directly inhibited the activation of stellate cells without affecting cellular proliferation and apoptosis. Indirectly, IFN-α treatment recruited many hepatic macrophages to locate around the fibrotic region in the cirrhotic liver. These IFN-α-induced macrophages exhibited stronger in vitro cytotoxicity against HSCs than the macrophages from untreated animals. Our preliminary data showed that increased expression of matrix metalloproteinase-7 (MMP-7) may contribute to this ability. Furthermore, IFN-α treatment stimulated the expression of matrix metalloproteinase-13 (MMP-13) in both HSCs and hepatic macrophages, which might explain the resolution of liver fibrosis after IFN-α gene therapy. By clarifying the underlying mechanisms involved in the therapeutic effects of IFN-α, we hope to provide a new insight into the treatment of liver cirrhosis.