Defining the distinct, intrinsic properties of the novel type i interferon, IFNϵ

Sebastian A. Stifter, Antony Y. Matthews, Niamh E. Mangan, Ka Yee Fung, Alexander Drew, Michelle D. Tate, Tatiana P. Soares Da Costa, Daniel Hampsey, Jemma Mayall, Phil M. Hansbro, Albert Garcia Minambres, Sahar G. Eid, Johnson Mak, Judy Scoble, George Lovrecz, Nicole A. DeWeerd, Paul J. Hertzog

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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.

Original languageEnglish
Pages (from-to)3168-3179
Number of pages12
JournalJournal of Biological Chemistry
Volume293
Issue number9
DOIs
Publication statusPublished - 1 Jan 2018

Cite this

Stifter, Sebastian A. ; Matthews, Antony Y. ; Mangan, Niamh E. ; Fung, Ka Yee ; Drew, Alexander ; Tate, Michelle D. ; Soares Da Costa, Tatiana P. ; Hampsey, Daniel ; Mayall, Jemma ; Hansbro, Phil M. ; Minambres, Albert Garcia ; Eid, Sahar G. ; Mak, Johnson ; Scoble, Judy ; Lovrecz, George ; DeWeerd, Nicole A. ; Hertzog, Paul J. / Defining the distinct, intrinsic properties of the novel type i interferon, IFNϵ. In: Journal of Biological Chemistry. 2018 ; Vol. 293, No. 9. pp. 3168-3179.
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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.",
author = "Stifter, {Sebastian A.} and Matthews, {Antony Y.} and Mangan, {Niamh E.} and Fung, {Ka Yee} and Alexander Drew and Tate, {Michelle D.} and {Soares Da Costa}, {Tatiana P.} and Daniel Hampsey and Jemma Mayall and Hansbro, {Phil M.} and Minambres, {Albert Garcia} and Eid, {Sahar G.} and Johnson Mak and Judy Scoble and George Lovrecz and DeWeerd, {Nicole A.} and Hertzog, {Paul J.}",
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Stifter, SA, Matthews, AY, Mangan, NE, Fung, KY, Drew, A, Tate, MD, Soares Da Costa, TP, Hampsey, D, Mayall, J, Hansbro, PM, Minambres, AG, Eid, SG, Mak, J, Scoble, J, Lovrecz, G, DeWeerd, NA & Hertzog, PJ 2018, 'Defining the distinct, intrinsic properties of the novel type i interferon, IFNϵ', Journal of Biological Chemistry, vol. 293, no. 9, pp. 3168-3179. https://doi.org/10.1074/jbc.M117.800755

Defining the distinct, intrinsic properties of the novel type i interferon, IFNϵ. / Stifter, Sebastian A.; Matthews, Antony Y.; Mangan, Niamh E.; Fung, Ka Yee; Drew, Alexander; Tate, Michelle D.; Soares Da Costa, Tatiana P.; Hampsey, Daniel; Mayall, Jemma; Hansbro, Phil M.; Minambres, Albert Garcia; Eid, Sahar G.; Mak, Johnson; Scoble, Judy; Lovrecz, George; DeWeerd, Nicole A.; Hertzog, Paul J.

In: Journal of Biological Chemistry, Vol. 293, No. 9, 01.01.2018, p. 3168-3179.

Research output: Contribution to journalArticleResearchpeer-review

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T1 - Defining the distinct, intrinsic properties of the novel type i interferon, IFNϵ

AU - Stifter, Sebastian A.

AU - Matthews, Antony Y.

AU - Mangan, Niamh E.

AU - Fung, Ka Yee

AU - Drew, Alexander

AU - Tate, Michelle D.

AU - Soares Da Costa, Tatiana P.

AU - Hampsey, Daniel

AU - Mayall, Jemma

AU - Hansbro, Phil M.

AU - Minambres, Albert Garcia

AU - Eid, Sahar G.

AU - Mak, Johnson

AU - Scoble, Judy

AU - Lovrecz, George

AU - DeWeerd, Nicole A.

AU - Hertzog, Paul J.

PY - 2018/1/1

Y1 - 2018/1/1

N2 - 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.

AB - 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.

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U2 - 10.1074/jbc.M117.800755

DO - 10.1074/jbc.M117.800755

M3 - Article

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JO - Journal of Biological Chemistry

JF - Journal of Biological Chemistry

SN - 1083-351X

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