Interferon epsilon (IFN-ε) is a type I IFN discovered in 2004. IFN-ε expression is independent of pattern recognition receptors and is not stimulated by viruses. Unlike IFN-α and IFN-β, IFN-ε is expressed primarily in mucosal tissues, mainly in the lungs, small intestine, and reproductive tissues. IFN-ε is highly expressed in the female reproductive tract, especially the uterus, cervix, vagina, and ovaries. Like IFN-α/β, IFN-ε binds to type I IFN receptors (IFNAR1 and IFNAR2).
IFN-Ε Expression is Regulated by Hormones and Seminal Fluid
- In different phases of the estrus cycle, the level of IFN-ε varies 30 times: during diestrus, IFN-ε levels are low, and during estrus, they are the highest.
- After estrogen administration, IFN-ε levels increase more than 6-fold.
- Progesterone suppresses the production of IFN-ε. A 2022 study in healthy women of reproductive age found that during the luteal phase of the menstrual cycle, IFN-ε levels were higher than during the follicular phase. IFN-ε levels differed between menstrual cycle phases in the endometrium but not in the vaginal epithelium and ectocervix. Progesterone, which predominates during the luteal phase, suppressed the expression of IFN-ε only in the endometrium since only in it progesterone receptors are expressed at a high level. Suppression of immune responses during the luteal phase is necessary to prepare the endometrium for embryo implantation. However, suppressing immune responses can make it easier to get sexually transmitted infections (STIs). Since IFN-ε protects against STIs and is dependent on progesterone levels, a question for future research is whether the use of hormonal contraceptives with high affinity for progesterone receptors may also suppress IFN-ε and whether this may affect susceptibility to STIs, including HIV.
Details of the study are in the article “Progesterone Inhibits Interferon Epsilon in The Female Reproductive Tract.” The study was published in JCI Insight. - Seminal fluid, the transport medium for sperm, increases the expression of IFN-ε in the tissues of the cervix and vagina.
Biological Properties of IFN-ε
IFN-ε has antiviral activity, but its action is much weaker than that of IFN-α and IFN-β. Thus, IFN-α stimulates the cytotoxicity of natural killer cells 60 times more strongly than IFN-ε. However, IFN-ε has broader cross-species activity and can affect many cells.
IFN-ε and IFN-α affect macrophages differently. IFN-α activates more genes in the type I IFN signaling pathway, and IFN-ε activates more genes in the TNF-α pathway, reactive oxygen species generation, and phagocyte activation, which contribute to suppressing HIV replication.
In addition to antiviral activity, IFN-ε has antiproliferative and antitumor effects.
IFN-ε is involved in the regulation of mucosal immune responses:
- A study in mice showed that IFN-ε levels in the lungs are increased during allergies.
- Intranasal infection with vaccinia virus coexpressing HIV and interferon epsilon caused rapid clearance of vaccinia with increased recruitment of lymphocytes to the lung alveoli with reduced inflammation. IFN-ε enhanced HIV-specific T cell responses but did not affect memory CD8+ T cell responses.
Viruses and Diseases Suppressed by IFN-ε
Vitiligo and Intracerebral Hemorrhages
IFN-ε is expressed in the brain and maintains brain structure and function. The hyaluronic acid receptor, the expression of which is stimulated by IFN-ε, is involved in the formation of brain microvessels.
A genetic mutation that impairs the synthesis of IFN-ε is associated with an increased risk of hemorrhagic stroke.
Vitiligo is a skin disease in which the melanocytes in the skin disappear. IFN-ε, which has inflammatory functions, is involved in developing vitiligo. A genetic mutation that impairs the synthesis of IFN-ε is associated with the early stages of non-segmental vitiligo.
Human Immunodeficiency Virus and Cervical Cancer
In reproductive tissues and especially the mucous membrane of the female genital organs, high expression of IFN-ε is observed. IFN-ε may be necessary in reproductive diseases such as HIV and cervical cancer (CC).
In cervical cancer cells, TNF-α stimulates IFN-ε production. IFN-ε mRNA expression is a potential marker of CC. IFN-ε can play an essential role in intracellular homeostasis and affect cervical carcinogenesis. CC is associated with human papillomavirus (HPV) infection, but IFN-ε expression is not associated with HPV infection.
IFN-ε may prevent transmission of HIV. Increased expression of the IFN-ε gene and its protein in the cervical epithelium is associated with decreased gene expression in HIV-1 entry and replication. Susceptibility to HIV varies during the menstrual cycle and drops when IFN-ε levels are higher. IFN-ε stimulates protein production that suppresses HIV early in the replication cycle. These results will help develop new HIV prevention strategies for women.
Zika Virus
The Zika virus is transmitted through mosquito bites and from person to person through sexual contact. As with HIV, IFN-ε suppresses the spread of the Zika virus. Among the reasons is the increased production of the IFITM protein in response to IFN-ε production. The same protein helps protect against HIV.
Herpes Simplex Virus type 2
Herpes simplex virus type 2 (HSV-2) is a sexually transmitted infection. A study in mice showed that, compared with controls, IFN-ε-deficient mice developed significantly more severe epidermal lesions on days 6 and 7 after HSV-2 infection. In infected vaginal tissues of IFN-ε-deficient mice, virus titers increased at day 3 post-infection, and at seven days post-infection, IFN-ε-deficient mice had significantly higher virus levels in the spinal cord and brainstem.
Chlamydia
Chlamydia muridarum is an intracellular bacterium that causes chlamydia in mice. Chlamydia is one of the most common sexually transmitted infections. IFN-ε-deficient mice infected with C. muridarum exhibited more severe clinical signs of disease 7 to 30 days post-infection. Also, more C. muridarum bacteria were found in vaginal swabs of these mice after infection, which means that IFN-ε may help treat some bacterial infections.
SARS-CoV-2 Coronavirus
Coronavirus can cause pneumonia and respiratory failure. The coronavirus death rate is higher in men than women due to high IFN-ε production in women.
IFN-ε plays a vital role in combating COVID-19. Children typically develop mild illness after contracting the coronavirus, but older adults are at risk for severe COVID-19. It occurs because preactivated innate immunity in children leads to a more effective antiviral response. Children and young adults infected with COVID-19 have significantly higher levels of IFN-ε and IFN-ω than older adults. Additionally, unlike children and young adults, older adults have elevated levels of interferon-stimulated genes (ISGs), which are associated with symptoms and the need for hospitalization.
Viruses and diseases unaffected by IFN-ε
Simian immunodeficiency virus (SIV)
A study in rhesus monkeys showed that SIV infection did not affect IFN-ε expression in the rectal mucosa.
Tuberculosis
Tuberculosis is a disease caused by Mycobacterium tuberculosis and most often affects the lungs. A study in rhesus monkeys showed that the level of IFN-ε mRNA expression in the blood does not affect M. tuberculosis infection and the severity of tuberculous lung disease.
Taylor murine encephalomyelitis virus (TMEV)
TMEV is used as a model to study the onset and progression of multiple sclerosis, an inflammatory demyelinating central nervous system disease. A mice study showed that intracellular IFN-ε expression does not protect against TMEV.
Mengovirus
Mengovirus is an encephalomyocarditis virus (EMCV) that frequently causes severe systemic and fatal infections in mice. In mice, after intraperitoneal injection of mengovirus, the spinal cord, brain, heart, and other organs were most infected after four days. In response to EMCV, IFN-β expression increased, but IFN-ε expression did not.
Premature birth
Premature birth is a leading cause of infant mortality. IFN-ε levels do not influence intrauterine infection or preeclampsia, which leads to preterm birth. Medical observations have shown that elevated levels of IFN-ε in women with preeclampsia increase the risk of preterm birth.
Conclusion
IFN-ε is essential in mucosal immunity and protection from viral and bacterial infections and some sexually transmitted diseases. IFN-ε may help develop new treatment strategies for conditions associated with immunodeficiency and reproductive infections, such as HIV and Zika.
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Reference
The regulation of antiviral activity of interferon epsilon
