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J Biol Chem. 2018 Mar 2;293(9):3168-3179. doi: 10.1074/jbc.M117.800755. Epub 2017 Nov 29.

Defining the distinct, intrinsic properties of the novel type I interferon, IFNϵ.

Author information

1
From the Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, 27-31 Wright Street, Clayton, Victoria 3168, Australia.
2
Department of Molecular and Translational Sciences, School of Clinical Sciences at Monash Health, Monash University, 27-31 Wright Street, Clayton, Victoria 3168, Australia.
3
Department of Biochemistry and Genetics, La Trobe Institute for Molecular Science, La Trobe University, Bundoora, Victoria 3086, Australia.
4
Priority Research Centre for Healthy Lungs, Hunter Medical Research Institute and University of Newcastle, Newcastle, New South Wales 2300, Australia.
5
School of Medicine, Deakin University, Geelong, Victoria 3220, Australia.
6
Commonwealth Scientific and Industrial Research Organisation (CSIRO) Australian Animal Health Laboratory, Geelong, Victoria 3220 Australia.
7
Institute for Glycomics, Griffith University, Gold Coast Campus, Southport, Queensland 4222, Australia, and.
8
CSIRO Manufacturing, Parkville, Victoria 3052, Australia.
9
From the Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, 27-31 Wright Street, Clayton, Victoria 3168, Australia, paul.hertzog@hudson.org.au.

Abstract

The type I interferons (IFNs) are a family of cytokines with diverse biological activities, including antiviral, antiproliferative, and immunoregulatory functions. The discovery of the hormonally regulated, constitutively expressed IFNϵ has suggested a function for IFNs in reproductive tract homeostasis and protection from infections, but its intrinsic activities are untested. We report here the expression, purification, and functional characterization of murine IFNϵ (mIFNϵ). Recombinant mIFNϵ (rmIFNϵ) exhibited an α-helical fold characteristic of type I IFNs and bound to IFNα/β receptor 1 (IFNAR1) and IFNAR2, but, unusually, it had a preference for IFNAR1. Nevertheless, rmIFNϵ induced typical type I IFN signaling activity, including STAT1 phosphorylation and activation of canonical type I IFN signaling reporters, demonstrating that it uses the JAK-STAT signaling pathway. We also found that rmIFNϵ induces the activation of T, B, and NK cells and exhibits antiviral, antiproliferative, and antibacterial activities typical of type I IFNs, albeit with 100-1000-fold reduced potency compared with rmIFNα1 and rmIFNβ. Surprisingly, although the type I IFNs generally do not display cross-species activities, rmIFNϵ exhibited high antiviral activity on human cells, suppressing HIV replication and inducing the expression of known HIV restriction factors in human lymphocytes. Our findings define the intrinsic properties of murine IFNϵ, indicating that it distinctly interacts with IFNAR and elicits pathogen-suppressing activity with a potency enabling host defense but with limited toxicity, appropriate for a protein expressed constitutively in a sensitive mucosal site, such as the reproductive tract.

KEYWORDS:

immunology; innate immunity; interferon; protein expression; signal transduction

PMID:
29187603
PMCID:
PMC5836118
[Available on 2019-03-02]
DOI:
10.1074/jbc.M117.800755

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