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

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

Author information

1
Department of Pathology and Molecular Medicine, McMaster Immunology Research Centre, Hamilton, ON, Canada; MG DeGroote Institute for Infectious Disease Research, McMaster Immunology Research Centre, Hamilton, ON L8N 3Z5, Canada.
2
Toronto Centre for Liver Disease, University Health Network, University of Toronto, ON, Canada.
3
Immunology and Infectious Diseases, Faculty of Medicine, Memorial University of Newfoundland, St. John's, Newfoundland, Canada.
4
Department of Pathology and Molecular Medicine, McMaster Immunology Research Centre, Hamilton, ON, Canada; MG DeGroote Institute for Infectious Disease Research, McMaster Immunology Research Centre, Hamilton, ON L8N 3Z5, Canada. Electronic address: ashkara@mcmaster.ca.

Abstract

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

PMID:
29908921
DOI:
10.1016/j.cyto.2018.06.006

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