mBio:HBV蛋白HBx促进肝炎新机制

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      近日，北京微生物学流行病学研究所在美国微生物学会开放获取网络期刊《mBio》发表题为“Upregulation of MicroRNA-146a by Hepatitis B Virus X Protein Contributes to Hepatitis Development by Downregulating Complement Factor H” 最新研究成果。


      研究人员发现在表达HBV蛋白的体外肝细胞和小鼠体内肝组织中，miR-146a（与先天免疫相关的一个miRNA）都是显著性上调表达的。进一步研究发现miR-146a上调表达是由HBV的HBx蛋白通过NF-kB信号通路介导的，而miR-146a上调表达导致了补体因子H（CFH，补体激活的替代途径的一个重要负调节因子）的表达显著下降，从而促进炎症的发生。这两个分子的基因水平在HBV病人肝组织中也得到了相同的结果验证。


      在这项研究中，研究人员对miR-146a和CFH在HBV相关肝脏炎症中所起的作用，进行了详细的分析，发现HBx-miR-146a-CFH-补体激活调节途径，可能在慢性HBV感染的发病机制中起重要作用。这一发现，对于了解慢性乙型肝炎的免疫发病机制和开发有效的治疗干预措施具有重要的意义。

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Upregulation of MicroRNA-146a by Hepatitis B Virus X Protein Contributes to Hepatitis Development by Downregulating Complement Factor H

• Jun-Feng Lia,
• Xiao-Peng Daia,
• Wei Zhanga,
• Shi-Hui Suna,
• Yang Zenga,
• Guang-Yu Zhaoa,
• Zhi-Hua Koua,
• Yan Guoa,
• Hong Yua,
• Lan-Ying Dub,
• Shi-Bo Jiangb,c,
• Yu-Sen Zhoua
  

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Author Affiliations

• [size=0.85em]aThe State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Microbiology and Epidemiology, Beijing, China
• [size=0.85em]bLaboratory of Viral Immunology, Lindsley F. Kimball Research Institute, New York Blood Center, New York, New York, USA
• [size=0.85em]cKey Laboratory of Medical Molecular Virology of Ministries of Education and Health, Shanghai Medical College, Fudan University, Shanghai, China
  

• Address correspondence to Yu-Sen Zhou, yszhou@bmi.ac.cn.
  

• Invited Editor John M. Taylor, Fox Chase Cancer Center Editor Michael J. Imperiale, University of Michigan
  
  

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ABSTRACT

Hepatic injuries in hepatitis B virus (HBV) patients are caused by immune responses of the host. In our previous study, microRNA-146a (miR-146a), an innate immunity-related miRNA, and complement factor H (CFH), an important negative regulator of the alternative pathway of complement activation, were differentially expressed in HBV-expressing and HBV-free hepatocytes. Here, the roles of these factors in HBV-related liver inflammation were analyzed in detail. The expression levels of miR-146a and CFH in HBV-expressing hepatocytes were assessed via analyses of hepatocyte cell lines, transgenic mice, adenovirus-infected mice, and HBV-positive human liver samples. The expression level of miR-146a was upregulated in HBV-expressing Huh-7 hepatocytes, HBV-expressing mice, and patients with HBV infection. Further results demonstrated that the HBV X protein (HBx) was responsible for its effects on miR-146a expression through NF-κB-mediated enhancement of miR-146a promoter activity. HBV/HBx also downregulated the expression of CFH mRNA in hepatocyte cell lines and the livers of humans and transgenic mice. Furthermore, overexpression and inhibition of miR-146a in Huh-7 cells downregulated and upregulated CFH mRNA levels, respectively. Luciferase reporter assays demonstrated that miR-146a downregulated CFH mRNA expression in hepatocytes via 3′-untranslated-region (UTR) pairing. The overall effect of this process in vivo is to promote liver inflammation. These results demonstrate that the HBx–miR-146a–CFH–complement activation regulation pathway might play an important role in the immunopathogenesis of chronic HBV infection. These findings have important implications for understanding the immunopathogenesis of chronic hepatitis B and developing effective therapeutic interventions.

http://mbio.asm.org/content/6/2/e02459-14.full

cao1976

路过，学习了。