Analysis of induction of chronic hepatitis by HCV infection

尽管在急慢性丙型肝炎患者的肝脏中观察到淋巴细胞和自然杀伤细胞的浸润，但丙型肝炎病毒（HCV）感染期间肝损伤的机制尚不清楚。干扰素-γ-诱导蛋白10（IP-10），选择性地招募活化的T细胞到炎症部位，已显示在慢性丙型肝炎患者的肝脏中表达。我们以前已经表明，IP-10的生产显着增强在HCV RNA复制子细胞和感染HCV的人肝癌细胞系通过TLR 2依赖的信号通路。通过DNA微阵列分析，我们已经确定CD 44是通过TLR信号通路参与炎症反应的候选者之一。CD 44是广泛分布的I型跨膜糖蛋白，是糖胺聚糖透明质酸（HA）的受体。HA也作为TLR 2的配体起作用，并且慢性丙型肝炎患者中的血清HA水平显示出根据肝纤维化的进展而增加。IP-10的产生也诱导了复制子细胞中的HA的处理，但不是在幼稚细胞。这些结果表明，IP-10的生产在HCV复制子细胞的HA刺激通过TLR 2和CD 44的参与，并在慢性丙型肝炎患者的血清HA参与诱导IP-10的调节。

Although infiltration of lymphocytes and natural killer cells was observed in the liver of acute and chronic hepatitis C patients, the mechanisms of the liver injury during hepatitis C virus (HCV) infection are not well understood. Interferon-gamma-inducible protein 10 (IP-10), that selectively recruits activated T cells to the sites of inflammation, has shown to be expressed in the livers of the chronic hepatitis C patients. We have shown previously that IP-10 production was significantly enhanced in HCV RNA replicon cells and the human hepatoma cell lines infected with HCV through a TLR2-dependent signaling pathway. By the DNA microarray analysis, we have identified CD44 as a one of the candidates involved in the inflammatory response through a TLR signaling pathway. CD44 is a broadly distributed type I transmembrane glycoprotein and a receptor for glycosaminoglycan hyaluronan (HA). HA also works as a ligand for TLR2 and serum HA levels in the chronic hepatitis C patients were shown to increase according to the progression of liver fibrosis. IP-10 production was also induced by the treatment with HA in the replicon cells, but not in the naive cells. These results suggest that the IP-10 production in the HCV replicon cells is regulated by HA stimulation through the engagement of TLR2 and CD44, and that serum HA in chronic hepatitis C patients participates in the induction of IP-10.