Oncotarget

Research Papers:

Hepatic NK cell-mediated hypersensitivity to ConA-induced liver injury in mouse liver expressing hepatitis C virus polyprotein

Qiuxia Fu, Shaoduo Yan, Licui Wang, Xiangguo Duan, Lei Wang, Yue Wang, Tao Wu, Xiaohui Wang, Jie An, Yulong Zhang, Qianqian Zhou and Linsheng Zhan _

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Oncotarget. 2017; 8:52178-52192. https://doi.org/10.18632/oncotarget.11052

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Abstract

Qiuxia Fu1,*, Shaoduo Yan1,*, Licui Wang1, Xiangguo Duan2, Lei Wang1, Yue Wang1, Tao Wu3, Xiaohui Wang1, Jie An1, Yulong Zhang1, Qianqian Zhou1, Linsheng Zhan1

1Beijing Institute of Transfusion Medicine, Beijing Key Laboratory of Blood Safety and Supply Technologies, Beijing, China

2Surgical Laboratory of General Hospital, Ningxia Medical University, Yinchuan, China

3Blood Transfusion Department, General Hospital of Beijing Military Area Command of PLA, Beijing, China

*These authors have contributed equally to this work

Correspondence to:

Linsheng Zhan, email: lszhan91@yahoo.com

Keywords: HCV, codon-optimized φC31 integrase, NK cells, liver injury

Received: December 13, 2015    Accepted: July 18, 2016    Published: August 04, 2016

ABSTRACT

The role of hepatic NK cells in the pathogenesis of HCV-associated hepatic failure is incompletely understood. In this study, we investigated the effect of HCV on ConA-induced immunological hepatic injury and the influence of HCV on hepatic NK cell activation in the liver after ConA administration. An immunocompetent HCV mouse model that encodes the entire viral polyprotein in a liver-specific manner based on hydrodynamic injection and φC31o integrase was used to study the role of hepatic NK cells. Interestingly, the frequency of hepatic NK cells was reduced in HCV mice, whereas the levels of other intrahepatic lymphocytes remained unaltered. Next, we investigated whether the reduction in NK cells within HCV mouse livers might elicit an effect on immune-mediated liver injury. HCV mice were subjected to acute liver injury models upon ConA administration. We observed that HCV mice developed more severe ConA-induced immune-mediated hepatitis, which was dependent on the accumulated intrahepatic NK cells. Our results indicated that after the administration of ConA, NK cells not only mediated liver injury through the production of immunoregulatory cytokines (IFN-γ, TNF-α and perforin) with direct antiviral activity, but they also killed target cells directly through the TRAIL/DR5 and NKG2D/NKG2D ligand signaling pathway in HCV mice. Our findings suggest a critical role for NK cells in oversensitive liver injury during chronic HCV infection.


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