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PLoS One. 2014 Jul 21;9(7):e103008. doi: 10.1371/journal.pone.0103008. eCollection 2014.

Tumor necrosis factor-alpha induced by hepatitis B virus core mediating the immune response for hepatitis B viral clearance in mice model.

Author information

1
Graduate Institute of Immunology, College of Medicine, National Taiwan University, Taipei, Taiwan.
2
Department of Internal Medicine, Taipei Medical University Shuang Ho Hospital, Taipei, Taiwan; Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.
3
Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan.
4
Department of Biochemical Science and Technology, National Taiwan University, Taipei, Taiwan.
5
Department of Microbiology, College of Medicine, National Taiwan University, Taipei, Taiwan; Graduate Institute of Clinical Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan.
6
Graduate Institute of Immunology, College of Medicine, National Taiwan University, Taipei, Taiwan; Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan.

Abstract

Persistent hepatitis B viral (HBV) infection results in chronic hepatitis, liver cirrhosis, and hepatocellular carcinoma (HCC). An efficient control of virus infections requires the coordinated actions of both innate and adaptive immune responses. In order to define the role of innate immunity effectors against HBV, viral clearance was studied in a panel of immunodeficient mouse strains by the hydrodynamic injection approach. Our results demonstrate that HBV viral clearance is not changed in IFN-α/β receptor (IFNAR), RIG-I, MDA5, MYD88, NLRP3, ASC, and IL-1R knock-out mice, indicating that these innate immunity effectors are not required for HBV clearance. In contrast, HBV persists in the absence of tumor necrosis factor-alpha (TNF-α) or in mice treated with the soluble TNF receptor blocker, Etanercept. In these mice, there was an increase in PD-1-expressing CD8+ T-cells and an increase of serum HBV DNA, HBV core, and surface antigen expression as well as viral replication within the liver. Furthermore, the induction of TNF-α in clearing HBV is dependent on the HBV core, and TNF blockage eliminated HBV core-induced viral clearance effects. Finally, the intra-hepatic leukocytes (IHLs), but not the hepatocytes, are the cell source responsible for TNF-α production induced by HBcAg. These results provide evidences for TNF-α mediated innate immune mechanisms in HBV clearance and explain the mechanism of HBV reactivation during therapy with TNF blockage agents.

PMID:
25047809
PMCID:
PMC4105421
DOI:
10.1371/journal.pone.0103008
[Indexed for MEDLINE]
Free PMC Article

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