miR146a impairs the IFN-induced anti-HBV immune response by downregulating STAT1 in hepatocytes
Article first published online: 24 JUL 2013
© 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
Volume 34, Issue 1, pages 58–68, January 2014
How to Cite
Liver Int. 2014: 34:58–68
- Issue published online: 10 DEC 2013
- Article first published online: 24 JUL 2013
- Accepted manuscript online: 16 JUN 2013 05:54AM EST
- Manuscript Accepted: 9 JUN 2013
- Manuscript Received: 4 JAN 2013
- National Natural Science Foundation of China. Grant Numbers: 30972692, 81172789
- National Basic Research Program of China. Grant Numbers: 2006CB504303, 2013CB531503, 2008ZX10002008, 2012ZX10002006
- HBV ;
- innate immunity;
- type I interferon
Background & Aims
Previous studies have shown that hepatitis B virus (HBV) interferes with host antiviral immunity via multiple pathways. In clinical practice, interferon resistance is a serious issue for treatment of HBV infection. Now, miRNAs have been reported to be widely involved in antiviral immunity and have become a novel tool to study virus–host interaction. We question whether miRNAs play a role in HBV-induced interferon resistance in hepatocytes.
MiRNAs levels in HepG2 and HepG2.2.15 cells were compared by qRT-PCR. The effects of miR146a on HBV infection were characterized by interference miR146a level, followed by the quantification of HBV mRNA, DNA and antigens. We employed qRT-PCR and western blot to study the effects of miR146a on the IFN-α signalling pathway. The miR146a promoter activity was validated by a luciferase reporter assay.
HBV infection impaired IFN-α signalling pathway in hepatocytes. MiR146a was upregulated in HBV+ HepG2.2.15 cells, and the transcriptional activity of miR146a in HepG2.2.15 cells was increased compared with HepG2 cells. HBV infection, especially the introduction of HBx, induced miR146a expression in vitro. Moreover, miR146a attenuated the production of type I interferon-induced antiviral factors. Low STAT1 levels were noticed in HBV+ HCC cells, and the luciferase reporter assay showed that STAT1 was post-transcriptionally downregulated by miR146a. Furthermore, the silencing of miR146a by antisense inhibitors enhanced IFN-α-mediated anti-HBV efficiency.
Our findings demonstrate that HBV infection promotes miR146a transcription, which represses STAT1 and results in interferon resistance. These observations reveal a novel role for miR146a in HBV immunopathogenesis, and provide a potential target for the therapeutic recovery of IFN-α-induced anti-HBV effects.