HCV诱导YKL-40表达正反馈促进病毒复制和肝纤维化的机制研究

Chronic infection with hepatitis C virus (HCV) causes liver with chronic inflammation, necrosis and fibrosis. Recurrent inflammatory lesions and activation of inflammatory signaling pathway are major contributors to start and promote the progression of liver fibrosis. We previously found that HCV induced the activation of NF-κB though the cooperation of ROS and TNF-α, subsequently leading to enhancement of YKL-40. However, neither small molecule inhibitor of NF-κB nor specific siRNAs against NF-κB can completely abrogate HCV-induced enhancement of YKL-40 expression. We further investigated that TLR4 agonist LPS-EK increased YKL-40 expression. Therefore, we will explore that whether TLR4-MyD88-AP1 signaling is involved in YKL-40 enhancement using real-time PCR, Western blot, and ELISA. Further experiments are needed to determine whether a YKL-40-dependent or IL-13RA2-AP1-TGF-β1-dependent manner mediates the YKL-40-induced enhancement of HCV replication and the expression of fibrosis-related genes. These support a potential mechanism by which HCV-induced enhancement of YKL-40 expression reciprocally promotes HCV replication and stimulates hepatocyte profibrogenic cytokine release.

丙型肝炎病毒(HCV)慢性感染可导致肝脏炎症坏死和纤维化。反复炎症损伤和炎症信号通路激活是启动和促进肝纤维化进展的重要因素。我们研究发现HCV诱导TNF-α和ROS增高，TNF-α随后联合ROS活化的ERK和p38 MAPK，三者通过NF-κB活化诱导炎症因子YKL-40的升高。但NF-κB 抑制不能完全阻断YKL-40的升高，表明存在其他通路参与YKL-40表达。进而发现YKL-40蛋白促进HCV复制和肝纤维化，其分子机制不得而知。在本研究中，我们采用Real-time PCR、免疫印迹和ELISA等方法研究TLR4-MyD88-AP1通路是否参与HCV诱导的YKL-40表达。探索YKL-40蛋白促HCV复制和肝纤维化是依赖YKL-40自身还是通过IL-13RA2-AP1-TGF-β1途径。从分子水平阐述HCV诱导YKL-40累积增加进而正反馈促进HCV复制和肝纤维化因子释放的机制。

丙型肝炎病毒(HCV)慢性感染可导致肝脏炎症坏死和纤维化。反复炎症损伤和炎症信号通路激活是启动和促进肝纤维化进展的重要因素。在本研究中，我们采用Real-time PCR、免疫印迹和ELISA等方法研究证实：HCV通过三条途径： 1. 氧化应激途径，即ROS-MAPKs (JNK/ERK/p38MAPK); 2. TNF-α; 3.LPS-TLR4-MyD88-TRAF6-AP-1三条途径共同活化NF-κB。活化的NF-κB随后诱导YKL-40产生。YKL-40进而通过IL-13RA2-AP1通路诱导TGF-β1释放增加，同时二者协同正反馈促进HCV复制和肝纤维化因子释放，形成不断活化的炎症级联反应，导致YKL-40的累积增加、HCV复制和肝纤维不断加重。本项目从分子水平阐述HCV诱导YKL-40累积增加进而正反馈促进HCV复制和肝纤维化因子释放的机制。