Research Article | Published:

Hepatic and Pancreatic Systems

Hepatitis B core antigen upregulates B7-H1 on dendritic cells by activating the AKT/ERK/P38 pathway: a possible mechanism of hepatitis B virus persistence

Laboratory Investigation volume 96, pages 11561164 (2016) | Download Citation

Abstract

B7-H1 binding to programmed death-1 may deliver a coinhibitory signal to T cells that is involved in the regulation of T-cell activation and tolerance. B7-H1 plays a key role in dysfunction of dendritic cells (DCs) during chronic HBV infection, but the expression mechanism of B7-H1 remains unclear. One hundred and twenty-nine patients with chronic HBV infection were categorized into either the immune tolerance phase (HBV-IT), the immune clearance phase (HBV-IC), or the inactive carrier phase (HBV-IA). Twenty healthy volunteers were enrolled as controls. Another 16 patients with HBeAg-positive chronic Hepatitis B were enrolled, and entecavir was administrated at 0.5 mg per day for 6 months. The B7-H1 expression level on peripheral DCs was tested by flow cytometry. In vitro, expression levels of B7-H1 and signaling molecules on monocyte-derived DC (MO-DC) induced by recombinant hepatitis B virus C antigen (rhHBcAg) were examined by RT-PCR, flow cytometry, and western blotting, and the apoptosis rate was tested by flow cytometry. The percentages of peripheral DCs and myeloid DCs (mDCs) were decreased and B7-H1 levels were increased in patients compared with controls. Serum HBV-DNA levels were positively correlated with B7-H1 levels on mDCs in patients with HBV-IT. B7-H1 levels on peripheral DCs from patients with chronic hepatitis B decreased after antiviral therapy. In vitro studies demonstrated that the B7-H1 level on MO-DC was upregulated by rhHBcAg, which resulted from the activation of PI3K–AKT, ERK, and P38 signaling pathways, and the percentage of MO-DC was downregulated by rhHBcAg. In addition, rhHBcAg promoted the apoptosis of MO-DC. The data suggest that HBcAg induced B7-H1 upregulation by activating AKT, ERK, and P38 signaling pathways, which inhibited the clearance of HBV-DNA and the reduction of DCs contributed to immune tolerance, which may correlate with apoptosis.

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Acknowledgements

This work was supported by the National Natural Science Foundation of China (81202662, 81473477, 81403354, 81473629, 81403351 and 81503545) and Science Research Project of Twelve Five-year Plan (2012ZX10005004-002) and Three-year action plan of development of TCM in Shanghai (ZYSNXD-CC-ZDYJ015 and ZY3-CCCX-3-3027) and Training plan of outstanding young medical talents, Shanghai Municipal Health Bureau (XYQ2013093).

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Author notes

    • Zhen-Hua Zhou

    These authors contributed equally to this work.

Affiliations

  1. Laboratory of Cellular Immunity, Shuguang Hospital, Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, PR China

    • Man Li
    • , Zhen-Hua Zhou
    • , Xin Zhang
    • , Shu-Gen Jin
    • , Ya-Ting Gao
    •  & Yue-Qiu Gao
  2. Department of Hepatopathy, Shuguang Hospital, Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, PR China

    • Xue-Hua Sun
    • , Xiao-Jun Zhu
    • , Yun Jiang
    •  & Yue-Qiu Gao

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The authors declare no conflict of interest.

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Correspondence to Yue-Qiu Gao.

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DOI

https://doi.org/10.1038/labinvest.2016.96

Supplementary Information accompanies the paper on the Laboratory Investigation website (http://www.laboratoryinvestigation.org)

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