Chung Shan Medical University, Taichung, Taiwan, Republic of China.
J Cell Biochem. 2011 Jan;112(1):233-43. doi: 10.1002/jcb.22926.
Chronic infection of hepatitis C virus (HCV) leads to hepatic fibrosis and subsequently cirrhosis, although the underlying mechanisms have not been established. Previous studies have indicated that the binding of HCV E2 protein and CD81 on the surface of hepatic stellate cells (HSCs) lead to the increased protein level and activity of matrix metallopeptidase (MMP) 2, indicating that E2 may involve in the HCV-induced fibrosis. This study was designed to investigate the involvement of HCV E2 protein in the hepatic fibrogenesis. Results showed that E2 protein may promote the expression levels of α-smooth muscle actin (α-SMA) and collagen α(I). Furthermore, several pro-fibrosis or pro-inflammatory cytokines, including transforming growth factor (TGF)-β1, connective tissue growth factor (CTGF), interleukin (IL)-6 and IL-1β, were significantly increased in E2 transfected-HSC cell lines, while the expression of MMP-2 are also considerably increased. Moreover, the significant increases of CTGF and TGF-β1 in a stable E2-expressing Huh7 cell line were also observed the same results. Further molecular studies indicated that the impact of E2 protein on collagen production related to higher production of ROS and activated Janus kinase (JAK)1, JAK2 and also enhance the activation of ERK1/2 and p38, while catalase and inhibitors specific for JAK, ERK1/2, and p38 abolish E2-enhanced expression of collagen α(I). Taken together, this study indicated that E2 protein involve in the pathogenesis of HCV-mediated fibrosis via an up-regulation of collagen α(I) and oxidative stress, which is JAK pathway related.
慢性丙型肝炎病毒（HCV）感染可导致肝纤维化，进而发展为肝硬化，但其潜在机制尚未明确。先前的研究表明，HCV E2 蛋白与肝星状细胞（HSCs）表面的 CD81 结合，导致基质金属蛋白酶（MMP）2 的蛋白水平和活性增加，表明 E2 可能参与 HCV 诱导的纤维化。本研究旨在探讨 HCV E2 蛋白在肝纤维化形成中的作用。结果表明，E2 蛋白可能促进α-平滑肌肌动蛋白（α-SMA）和胶原α（I）的表达水平。此外，在转染 E2 的 HSC 细胞系中，几种促纤维化或促炎细胞因子，包括转化生长因子（TGF）-β1、结缔组织生长因子（CTGF）、白细胞介素（IL）-6 和 IL-1β，表达水平显著增加，同时 MMP-2 的表达也明显增加。此外，在稳定表达 E2 的 Huh7 细胞系中，CTGF 和 TGF-β1 的表达也显著增加，得到了相同的结果。进一步的分子研究表明，E2 蛋白对胶原产生的影响与 ROS 产量增加以及 Janus 激酶（JAK）1、JAK2 的激活有关，同时还增强了 ERK1/2 和 p38 的激活，而 CAT 酶和针对 JAK、ERK1/2 和 p38 的抑制剂可消除 E2 增强的胶原α（I）表达。综上所述，本研究表明，E2 蛋白通过上调胶原α（I）和氧化应激参与 HCV 介导的纤维化发病机制，这与 JAK 途径有关。
