Embryotoxic cytokines—Potential roles in embryo loss and fetal programming

• Published in: Journal of reproductive immunology 2018-02, Vol.125, p.80-88
• Main Authors: Robertson, Sarah A., Chin, Peck-Yin, Femia, Joseph G., Brown, Hannah M.
• Format: Article
• Language: English
• Subjects: Apoptosis; Cytokines; Embryo; IFNG; Stress response; TNF; TRAIL
• ISSN: 0165-0378; 1872-7603
• DOI: 10.1016/j.jri.2017.12.003

•As well as embryotrophic cytokines, the maternal reproductive tract can secrete embryotoxic cytokines including TNF, TRAIL and IFNG.•Embryotoxic cytokines can be elevated in reproductive and systemic inflammatory conditions including infection, diabetes, obesity, PCOS and endometriosis.•Embryotoxic cytokines may contribute to unexplained infertility, as well as embryonic programming of fetal growth restriction and metabolic disorder in offspring. Cytokines in the reproductive tract environment at conception mediate a dialogue between the embryo and maternal tissues to profoundly influence embryo development and implantation success. Through effects on gene expression and the cell stress response, cytokines elicit an epigenetic impact with consequences for placental development and fetal growth, which in turn affect metabolic phenotype and long-term health of offspring. There is substantial evidence demonstrating that pro-survival cytokines, such as GM-CSF, CSF1, LIF, HB-EGF and IGFII, support embryos to develop optimally. Less attention has been paid to cytokines that adversely impact embryo development, including the pro-inflammatory cytokines TNF, TRAIL and IFNG. These agents elicit cell stress, impair cell survival and retard blastocyst development, and at sufficiently high concentrations, can cause embryo demise. Experiments in mice suggest these so-called ‘embryotoxic’ cytokines can harm embryos through pro-apoptotic and adverse programming effects, as well as indirectly suppressing uterine receptivity through the maternal immune response. Embryotrophic factors may mitigate against and protect from these adverse effects. Thus, the balance between embryotrophic and embryotoxic cytokines can impart effects on embryo development and implantation, and has the potential to contribute to endometrial ‘biosensor’ function to mediate embryo selection. Embryotoxic cytokines can be elevated in plasma and reproductive tract tissues in inflammatory conditions including infection, diabetes, obesity, PCOS and endometriosis. Studies are therefore warranted to investigate whether excessive embryotoxic cytokines contribute to infertility and recurrent implantation failure in women, and compromised reproductive performance in livestock animals.