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，但丙型肝炎病毒感染时肝损伤的机制尚不清楚。干扰素-γ诱导蛋白10(IP-10)选择性地将激活的T细胞招募到炎症部位，已被证明在慢性丙型肝炎患者的肝脏中表达。我们以前已经证明，在丙型肝炎病毒RNA复制子细胞和感染丙型肝炎病毒的人肝癌细胞系中，IP-10的产生通过依赖TLR2的信号通路显著增强。通过DNA微阵列分析，我们已经确定CD44是通过TLR信号通路参与炎症反应的候选分子之一。CD44是一种分布广泛的I型跨膜糖蛋白，是糖胺聚糖透明质酸(HA)的受体。HA也是TLR2的配基，慢性丙型肝炎患者的血清HA水平随着肝纤维化的进展而升高。HA可诱导复制子细胞产生IP-10，但不能诱导幼稚细胞产生IP-10。这些结果表明，丙型肝炎病毒复制子细胞中IP-10的产生受HA刺激通过TLR2和CD44的参与而调节，慢性丙型肝炎患者血清HA参与了IP-10的诱导。

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.