Get access

MicroRNA-155 controls Toll-like receptor 3- and hepatitis C virus-induced immune responses in the liver

Authors

  • M. Jiang,

    1. Faculty of Medicine, Department of Gastroenterology and Hepatology, University Duisburg-Essen, Essen, Germany
    2. Faculty of Medicine, Institute of Virology, University Duisburg-Essen, Essen, Germany
    3. Department of Infectious Disease, Union Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
    Search for more papers by this author
    • These authors contributed equally to this work.
  • R. Broering,

    1. Faculty of Medicine, Department of Gastroenterology and Hepatology, University Duisburg-Essen, Essen, Germany
    Search for more papers by this author
    • These authors contributed equally to this work.
  • M. Trippler,

    1. Faculty of Medicine, Department of Gastroenterology and Hepatology, University Duisburg-Essen, Essen, Germany
    Search for more papers by this author
  • J. Wu,

    1. Department of Infectious Disease, Union Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
    Search for more papers by this author
  • E. Zhang,

    1. Faculty of Medicine, Institute of Virology, University Duisburg-Essen, Essen, Germany
    2. Department of Infectious Disease, Union Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
    Search for more papers by this author
  • X. Zhang,

    1. Faculty of Medicine, Institute of Virology, University Duisburg-Essen, Essen, Germany
    2. Department of Infectious Disease, Union Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
    Search for more papers by this author
  • G. Gerken,

    1. Faculty of Medicine, Department of Gastroenterology and Hepatology, University Duisburg-Essen, Essen, Germany
    Search for more papers by this author
  • M. Lu,

    1. Faculty of Medicine, Institute of Virology, University Duisburg-Essen, Essen, Germany
    2. Department of Infectious Disease, Union Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
    Search for more papers by this author
  • J. F. Schlaak

    Corresponding author
    1. Faculty of Medicine, Department of Gastroenterology and Hepatology, University Duisburg-Essen, Essen, Germany
    • Correspondence: Joerg F. Schlaak, MD, Professor of Medicine, Department of Gastroenterology and Hepatology, University Hospital of Essen, Hufelandstr. 55, 45122 Essen, Germany.

      E-mail: joerg.schlaak@uni-due.de

    Search for more papers by this author

Summary

The hepatitis C virus (HCV) establishes persistent infections despite strong activation of the innate immune system through TLR3 and other sensors. Therefore, we analysed regulatory mechanisms of TLR3-induced immune responses in nonparenchymal liver cells (NPCs). Effects of Interleukin-10 (IL-10), transforming growth factor beta (TGF-β) and immunoregulatory miR-155 on poly I:C-activated murine (C57BL/6) Kupffer cells (KC) and sinusoidal endothelial cells (LSEC) were assessed in vitro. NPCs were assayed for inflammatory and antiviral cytokines and T-cell (Balb/c)-activating factors. Gene expression of miR-155, IL-10, TGF-β and interferon sensitive genes (ISGs) in biopsies of patients with HCV was determined by qrt-PCR. TLR3-induced antiviral activity in murine NPCs was potently suppressed by IL-10 and TGF-β which correlated with decreased TLR3 expression and inhibition of NF-κB and IRF-3 activation. T-cell activation, induced by TLR3-activated NPCs, was also suppressed by IL-10 and TGF-β, which was associated with a down-regulation of CD80 and CD86. Pretreatment with IL-10 or TGF-β suppressed TLR3-induced miR-155 expression, which itself positively regulated poly I:C-mediated immune responses, thus counteracting IL-10 or TGF-β-induced immunosuppression. In addition, hepatic expression of miR-155 was elevated in chronically infected patients with HCV, was associated with an IL-28B SNP (rs12979860) and was inversely correlated with HCV serum load and ISG expression levels. As miR-155 is a key regulator of anti-inflammatory mechanisms that control innate and adaptive hepatic immune responses during HCV infection, miR-155 based therapies may represent a novel mechanism to control HCV in the future.

Ancillary