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 language | English |
|---|---|
| Pages (from-to) | 3168-3179 |
| Number of pages | 12 |
| Journal | Journal of Biological Chemistry |
| Volume | 293 |
| Issue number | 9 |
| DOIs | |
| Publication status | Published - 1 Jan 2018 |
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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 journal › Article › Research › peer-review
TY - JOUR
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.
UR - http://www.scopus.com/inward/record.url?scp=85042880363&partnerID=8YFLogxK
U2 - 10.1074/jbc.M117.800755
DO - 10.1074/jbc.M117.800755
M3 - Article
AN - SCOPUS:85042880363
VL - 293
SP - 3168
EP - 3179
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
SN - 1083-351X
IS - 9
ER -