The female reproductive tract (hFRT) mucosa requires fine immune regulation. On the one hand, the immune system must reliably protect itself from influence and, on the other hand, maintain tolerance to commensal bacteria, sperm, and developing pregnancy.
The immune status of hFRT varies in different phases of the menstrual cycle and depends on the hormones estradiol (E2) and progesterone. During the luteal phase of the menstrual cycle, progesterone predominates. At this time, the endometrium prepares for fertilization and embryo implantation, so immune reactions are suppressed. However, immune suppression may lead to more manageable infections. Interestingly, a synthetic progestogen is used in animal studies to achieve high susceptibility to Chlamydia trachomatis and herpes simplex virus infections.
Type I interferons, including IFN-ε, can be used to prevent exposure. Epithelial cells lining the vagina, cervix, and endometrium mucosa produce both conventional type I IFN when exposed to a pathogen and the recently discovered IFN-ε, the production of which is independent of pathogen detection but dependent on hormones. In mice, IFN-ε orchestrates viral and bacterial sexually transmitted infections. Experiments on human cells have shown that IFN-ε can block HIV replication by stimulating the production of antiviral proteins.
In 2022, an international team of scientists examined how IFN-ε expression in hFRT decreases during the follicular and luteal phases of the menstrual cycle in healthy women of reproductive age with regular cycles.
Thirty-three women took part in the event. Mean serum progesterone levels are 49 and 6171 pg/ml for the follicular and luteal phases, respectively. IFN-ε was expressed throughout hFRT.
Study Results
- In the endometrium during the menstrual cycle’s luteal phase, the IFN-ε level was higher than during the follicular phase.
- IFN-ε levels did not differ between menstrual cycle phases in the vaginal epithelium and ectocervix.
- Progesterone suppresses IFN-ε expression. Progesterone receptors were expressed at high levels in the endometrium and low levels in the ectocervix and vagina. Progesterone receptor levels in the endometrium were lower during the luteal phase of the menstrual cycle. In an experiment on endometrial cells, progesterone stimulation suppressed IFN-ε expression, but estrogen stimulation of IFN-ε had no effect.
- IFN-ε regulated immune response protection in hFRT. Regardless of the menstrual cycle phase or cell type (vaginal, cervical, or endometrial), IFN-ε stimulates the expression of antiviral ISGs and chemokines in all cells. When ectocervical cells were stimulated with exogenous IFN-ε, ISH levels increased 10-100 times.
- IFN-ε is the only interferon highly expressed in the lining of the female reproductive tract. Although many interferons can regulate the immune response in hFRT, all other interferons were either undetectable or expressed at deficient levels compared to IFN-ε.
Conclusion
IFN-ε is the only interferon produced throughout the female reproductive tract at high levels in the endometrium, the site of embryo implantation.
IFN-ε regulates the mucosal innate immune system response and protects against ascending infections such as chlamydia. IFN-ε protects cervical and vaginal epithelium from HIV infection.
Progesterone suppresses IFN-ε expression in the endometrium but not in the vagina or ectocervix. The reason is that progesterone receptors are expressed at high levels only in the endometrium. In addition, progesterone receptor expression is regulated by estradiol. However, more research is needed to decipher the complex relationships between estrogen responses, progesterone receptors, and IFN-ε expression in the endometrium.
Since IFN-ε protects against sexually transmitted infections (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?
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Reference
Spatiotemporal regulation of human IFN-ε and innate immunity in the female reproductive tract
