信号转导子和转录激活子STAT4信号通路在T细胞介导的肝炎中保护机制的研究

Most cases of the chronic hepatitis are liver injury and inflammation caused by T cell-mediated immune response. The Janus Kinase-signal transducers and activators of transcription (JAk-STAT) signaling pathway has been shown to play crucial roles in hepatitis including viral hepatitis and autoimmune hepatitis. The roles of STAT4 in the pathogeneses of liver diseases are largely unknown, even though STAT1/2, STAT3 and STAT6 have been well proved to be very important in the progress of liver inflammation, fibrosis and cancer. In our previous study, we found much more activated STAT4 in the liver of patients with autoimmune hepatitis、hepatitis B and hepatitis C than that of health controls. Besides that, it is unexpected that more liver injury was found in STAT4 knockout mice compared with wild type mice. Based on these phenomenons, our hypothesis is: STAT4 is activated in the immune cells in ConA-induced hepatitis model and plays a protective role via regulation of inflammatory cytokines and inhibition of Fas/FasL in liver inflammatory response and liver injury. To validate the hypothesis, we plan to detect the level of activation of STAT4 in immune cells of serum and liver in various patients with hepatitis to evaluate the correlation of activated STAT4 and liver injury. To establish the animal model of ConA induced hepatitis and mouse primary hepatocyte culture system to identify the critical roles of STAT4 in the control of liver injury and liver inflammation. The project will be focus on the mechanisms of the activation and immune regulation of STAT4 in liver inflammatory response in order to provide theoretical and experimental evidences for the exploration of new drugs which target to STAT4 in the therapy of hepatitis.

JAK-STAT信号通路在肝脏炎症中至关重要。而STAT4作为其成员之一,却较少受到关注。我们前期研究发现几种慢性肝炎患者肝内均有大量STAT4激活，而健康者肝内鲜有STAT4激活现象，证实STAT4在肝炎中亦起重要作用。在进一步研究中，我们得到出人意料的发现：在ConA诱导的肝炎模型中，STAT4并不促炎，而是起到保护作用。由此我们推测:在肝脏炎症过程中，免疫细胞中的STAT4一方面通过调控细胞因子间接影响肝细胞损伤；同时STAT4还可能影响免疫细胞直接对靶细胞的杀伤作用。为验证此观点，本项目计划检测肝炎患者血清和肝内STAT4的活化情况，评价STAT4激活与肝脏炎症反应程度的相关性；同时在STAT4缺陷和野生型小鼠上建立ConA模型；建立体外原代肝细胞培养体系，明确STAT4激活的调控机制以及在疾病发展过程中的重要临床意义，为进一步寻找治疗肝脏炎症的新靶向药物提供理论和实验基础。

JAK-STAT信号通路在肝脏炎症中至关重要。而STAT4作为其成员之一，却较少被关注。既往的研究结果不统一，结论不一致。我们的研究发现几种慢性肝炎患者肝内均有大量STAT4激活，而健康者肝内鲜有STAT4激活现象，证实STAT4在肝炎中起重要作用。我们在进一步研究中意外发现：ConA诱导的肝炎模型中，STAT4并不促炎，而是起保护作用。由此我们推测在肝脏炎症过程中，免疫细胞上STAT4活化，并承担双重作用，在上调下游炎症细胞因子，间接影响肝细胞损伤的同时，影响免疫细胞NKT直接对靶细胞的杀伤作用从而在肝炎中起到保护、制衡的重要作用。为验证此观点，本项目从临床、动物实验两部分着手，评价STAT4激活与肝脏炎症反应程度的相关性；在STAT4基因敲除小鼠和野生型小鼠上建立ConA模型，并建立体外原代肝细胞培养体系，证实了我们的科学假说，证实在ConA诱导的肝炎模型中，STAT4被激活，一方面通过调控细胞因子促进肝细胞损伤；另一方面通过更有力地抑制NKT细胞的Fas/FasL系统，抑制肝细胞凋亡，最终在此炎症损伤过程中起到保护性作用。此结论总结发表论著1篇，发表在The American Journal of Pathology,另综述1篇，发表在International Journal of Biological Sciences. 相关研究内容和结果参加一次美国肝病年会、2次中华医学会感染病学分会年会、1次全国脂肪肝病学术会议、以及若干次省市级学术会议学术交流。在明确了STAT4激活的调控机制以及在肝脏炎症发展过程中的重要临床意义后，进一步进行STAT4在肝纤维化机制的作用研究，以期为寻找肝炎肝硬化治疗的新靶向药物提供理论和实验基础。