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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