白细胞介素-18介导的细胞信号转导与γ干扰素表达的乙肝病

StephenW

Downregulation of Interleukin-18-Mediated Cell Signaling and Interferon Gamma Expression by the Hepatitis B Virus e Antigen

    S. Jegaskandaa,
    S. H. Ahnb,c,
    N. Skinnere,f,
    A. J. Thompsonb,d,e,
    T. Ngyuenb,d,
    J. Holmesb,d,
    R. De Rosea,
    M. Navisa,
    W. R. Winnalla,
    M. Kramskia,
    G. Bernardia,
    J. Baylissb,
    D. Colledgeb,
    V. Sozzib,
    K. Visvanathane,f,
    S. A. Locarninib,
    S. J. Kenta and
    P. A. Revilla,b

    aDepartment of Microbiology and Immunology, Peter Doherty Institute, The University of Melbourne, Parkville, Victoria, Australia
    bDivision of Research and Molecular Development, Victorian Infectious Diseases Reference Laboratory, Peter Doherty Institute, Parkville, Victoria, Australia
    cDepartment of Internal Medicine, Yonsei University College of Medicine, Seoul, South Korea
    dDepartment of Gastroenterology, St. Vincent's Hospital, Fitzroy, Victoria, Australia
    eDepartment of Medicine, Eastern Hill Academic Centre, The University of Melbourne, Parkville, Victoria, Australia
    fDepartment of Infectious Diseases, St. Vincent's Hospital, Fitzroy, Victoria, Australia

    G. McFadden, Editor

- Author Affiliations
ABSTRACT

The mechanisms by which hepatitis B virus (HBV) establishes and maintains chronic hepatitis B infection (CHB) are poorly defined. Innate immune responses play an important role in reducing HBV replication and pathogenesis. HBV has developed numerous mechanisms to escape these responses, including the production of the secreted hepatitis B e antigen (HBeAg), which has been shown to regulate antiviral toll-like receptor (TLR) and interleukin-1 (IL-1) signaling. IL-18 is a related cytokine that inhibits HBV replication in hepatoma cell lines and in the liver through the induction of gamma interferon (IFN-γ) by NK cells and T cells. We hypothesized that HBV or HBV proteins inhibit IFN-γ expression by NK cells as an accessory immunomodulatory function. We show that HBeAg protein inhibits the NF-κB pathway and thereby downregulates NK cell IFN-γ expression. Additionally, IFN-γ expression was significantly inhibited by exposure to serum from individuals with HBeAg-positive but not HBeAg-negative chronic HBV infection. Further, we show that the HBeAg protein suppresses IL-18-mediated NF-κB signaling in NK and hepatoma cells via modulation of the NF-κB pathway. Together, these findings show that the HBeAg inhibits IL-18 signaling and IFN-γ expression, which may play an important role in the establishment and/or maintenance of persistent HBV infection.

IMPORTANCE It is becoming increasingly apparent that NK cells play a role in the establishment and/or maintenance of chronic hepatitis B infection. The secreted HBeAg is an important regulator of innate and adaptive immune responses. We now show that the HBeAg downregulates NK cell-mediated IFN-γ production and IL-18 signaling, which may contribute to the establishment of infection and/or viral persistence. Our findings build on previous studies showing that the HBeAg also suppresses the TLR and IL-1 signaling pathways, suggesting that this viral protein is a key regulator of antiviral innate immune responses.
FOOTNOTES

        Received 19 January 2014.
        Accepted 21 May 2014.
    Address correspondence to P. A. Revill, [email protected].

    S.J. and S.H.A. contributed equally to this study.

    Published ahead of print 28 May 2014

    Copyright © 2014, American Society for Microbiology. All Rights Reserved.

StephenW

白细胞介素-18介导的细胞信号转导与γ干扰素表达的乙肝病毒e抗原下调

    南Jegaskandaa，
    S.H。Ahnb，C，
    北Skinnere，F，
    A. J. Thompsonb，D，E，
    T. Ngyuenb，D，
    J. Holmesb，D，
    R.德糠疹，
    M. Navisa，
    W·R·Winnalla，
    M. Kramskia，
    G. Bernardia，
    J. Baylissb，
    D. Colledgeb，
    五，Sozzib，
    K. Visvanathane，F，
    S.A。Locarninib，
    S.J。健和
    P. A.雷维拉，B

    微生物学与免疫学，彼得·多尔蒂学院，墨尔本大学，帕克维尔，维多利亚，澳大利亚的aDepartment
    研究bDivision与分子发展，维多利亚传染病参考实验室，彼得·多尔蒂研究所，帕克维尔，维多利亚，澳大利亚
    内科，医学延世大学，首尔，韩国cDepartment
    消化内科，圣文森特医院，菲茨罗伊，维多利亚，澳大利亚的dDepartment
    医药，东森山庄学术中心，墨尔本大学，帕克维尔，维多利亚，澳大利亚的eDepartment
    传染病fDepartment，圣文森特医院，菲茨罗伊，维多利亚，澳大利亚

    G.麦克法登，编辑

- 作者所属机构
摘要

由B型肝炎病毒的机制（HBV）的建立和维护的慢性乙肝病毒感染（CHB）的定义不清。先天免疫反应在减少病毒复制和发病机理中起重要作用。乙肝病毒已经开发了许多机制来逃避这些反应，包括生产的分泌乙型肝炎e抗原（HBeAg），这已被证明是调节抗病毒toll样受体（TLR）和白细胞介素-1（IL-1）信令。 IL-18是一种相关的细胞因子，抑制HBV复制在肝癌细胞系中以及在通过γ干扰素（IFN-γ）的NK细胞和T细胞的诱导肝脏。我们推测，HBV或HBV蛋白抑制IFN-γ的表达NK细胞作为附件免疫调节功能。我们表明，e抗原蛋白抑制NF-κB途径，从而下调NK细胞的IFN-γ的表达。此外，IFN-γ的表达显著暴露于血清个人HBeAg阳性，但不HBeAg阴性的慢性HBV感染的抑制。此外，我们表明，在e抗原蛋白通过NF-κB途径的调制抑制IL-18介导的NF-κB信号传导在NK细胞和肝癌细胞。总之，这些结果表明，HBeAg的抑制IL-18信号传导和IFN-γ的表达，这可能在建立和/或维持的持久性HBV感染中起重要作用。

重要性现在越来越明显的是，NK细胞在建立和/或维持慢性乙型肝炎病毒感染的作用。所述分泌的HBeAg是先天和适应性免疫反应的重要调节剂。我们现在表明，HBeAg的下调NK细胞介导的IFN-γ的产生和IL-18的信号，这可能有助于建立感染和/或病毒的持久性。我们的研究结果建立在以前的研究显示，在e抗原也抑制TLR和IL-1信号通路，这表明该病毒蛋白是抗病毒先天免疫反应的重要调节器。
脚注

        收到2014年1月19日。
        接受2014年5月21日。
    通讯地址PA Revill，[email protected]。

    S.J。和S.H.A.同等贡献的研究。

    出版印刷28领先2014年5月

    ©版权所有2014年，美国微生物学会。版权所有。