IL-15 and IFN-γ signal through the ERK pathway to inhibit HCV replication, independent of type I IFN signaling

Cytokine. 2019 Dec;124:154439. doi: 10.1016/j.cyto.2018.06.006. Epub 2018 Jun 19.


Despite effective new treatments for Hepatitis C virus (HCV) infection, development of drug resistance, safety concerns and cost are remaining challenges. More importantly, there is no vaccine available against hepatitis C infection. Recent data suggest that there is a strong correlation between spontaneous HCV clearance and human NK cell function, particularly IFN-γ production. Further, IL-15 has innate antiviral activity and is also one of the main factors that activates NK cells to produce IFN-γ. To examine whether IL-15 and IFN-γ have direct antiviral activity against HCV, Huh7.5 cells were treated with either IFN-γ or IL-15 prior to HCV infection. Our data demonstrate that IFN-γ and IL-15 block HCV replication in vitro. Additionally, we show that IL-15 and IFN-γ do not induce anti-HCV effects through the type I interferon signaling pathway or nitric oxide (NO) production. Instead, IL-15 and IFN-γ provide protection against HCV via the ERK pathway. Treatment of Huh7.5 cells with a MEK/ERK inhibitor abrogated the anti-HCV effects of IL-15 and IFN-γ and overexpression of ERK1 prevented HCV replication compared to control transfection. Our in vitro data support the hypothesis that early production of IL-15 and activation of NK cells in the liver lead to control of HCV replication.

Keywords: Antiviral agents; Hepatitis C; Interferon type I; Interleukin-15 (IL-15); MAP kinase signaling system; Natural killer (NK) cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antiviral Agents / pharmacology
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Cell Proliferation / genetics
  • Hepacivirus / drug effects
  • Hepacivirus / immunology
  • Hepacivirus / physiology*
  • Humans
  • Immunity, Innate / drug effects
  • Interferon Type I / metabolism
  • Interferon Type I / pharmacology
  • Interferon-alpha / pharmacology
  • Interferon-gamma / pharmacology*
  • Interleukin-15 / pharmacology*
  • Killer Cells, Natural / immunology*
  • Liver / drug effects
  • Liver / immunology*
  • Liver / physiopathology
  • Liver / virology*
  • MAP Kinase Signaling System / drug effects
  • MAP Kinase Signaling System / genetics
  • MAP Kinase Signaling System / immunology*
  • Mitogen-Activated Protein Kinase 3 / antagonists & inhibitors
  • Mitogen-Activated Protein Kinase 3 / metabolism
  • Nitric Oxide / pharmacology
  • Up-Regulation
  • Virus Replication* / drug effects
  • Virus Replication* / genetics


  • Antiviral Agents
  • IL15 protein, human
  • Interferon Type I
  • Interferon-alpha
  • Interleukin-15
  • Nitric Oxide
  • Interferon-gamma
  • MAPK3 protein, human
  • Mitogen-Activated Protein Kinase 3

Grant support