Credit: GETTY

The previously uncharacterized interferon-ε (IFNε) is now shown by Paul Hertzog and colleagues to be a unique member of the type I IFN family that constitutively protects the female reproductive tract from bacterial and viral infections.

The other members of the type I IFN locus — the 13 IFNα subtypes, IFNβ and IFNω — are mainly expressed by haematopoietic cells in response to signalling through pattern recognition receptors. This leads to the activation of interferon-regulatory factors (IRFs) that bind to response elements in the type I IFN gene promoters. These type I IFNs transduce signals through the IFNα/β receptor (composed of IFNAR1 and IFNAR2 subunits), resulting in the induction of IFN-stimulated genes (ISGs). IFNε, which is also encoded in the type I IFN locus, has only 30% amino acid homology with IFNα and IFNβ, but the authors showed that it can signal through IFNAR1 and IFNAR2 to induce ISGs in macrophages and is therefore a bona fide member of the type I IFN family.

an important role for IFNε as a first line of defence to prevent the spread of viral and bacterial STIs

Surprisingly, however, IFNε expression could not be induced in various cell types by the activation of Toll-like receptors, retinoic acid-inducible gene I (RIG-I) or the inflammasome. Consistent with this, the Ifne promoter lacks IRF response elements, and IRFs could not induce the promoter activity of an Ifne-luciferase reporter. Instead, IFNε was shown to be constitutively expressed by luminal and glandular epithelial cells of the uterus, cervix, vagina and ovaries in mice. The level of IFNε varied at different stages of the oestrus cycle and was markedly decreased during pregnancy. IFNε expression was also decreased in pseudo-pregnant mice, which indicates that IFNε expression is regulated by maternal hormones rather than by embryonic factors. Indeed, the expression of IFNε (but not other type I IFNs) could be induced in ovariectomized mice by the administration of oestrogen and could be suppressed by the administration of progesterone. In human females, IFNε levels in endometrial samples were highest in the proliferative phase of the menstrual cycle (when oestrogen levels are highest) and lowest in postmenopausal women (when oestrogen levels are lowest).

In Ifne−/− mice, the basal levels of ISGs in the uterus were significantly lower than in wild-type mice, which led the authors to suggest that the constitutive expression of IFNε in the female reproductive tract is required to maintain ISG expression as a form of innate immune defence against sexually transmitted infections (STIs). Ifne−/− mice infected with herpes simplex virus 2 (HSV-2) or Chlamydia muridarum had more severe clinical disease than wild-type mice, as well as higher levels of virus or bacteria at defined time points after infection. HSV-2-infected Ifne−/− mice had higher viral titres in the spinal cord and the brain stem compared with wild-type mice, and C. muridarum-infected Ifne−/− mice had increased bacterial growth in the upper female reproductive tract compared with wild-type mice. Together, these results show an important role for IFNε as a first line of defence to prevent the spread of viral and bacterial STIs. The direct protective effect of IFNε against infection was shown by the administration of recombinant IFNε to mice that had been pretreated with progesterone to lower constitutive IFNε levels.

This unique role of IFNε in the female reproductive tract could have important future implications for treating STIs, particularly in women taking progestogen-containing forms of contraception, who are known to be more susceptible to infection of the reproductive tract.