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Relevance of placental type I interferon beta regulation for pregnancy success.

ABSTRACT: Pregnancy is a unique immunologic and microbial condition that requires an adequate level of awareness to provide a fast and protective response against pathogens as well as to maintain a state of tolerance to paternal antigens. Dysregulation of inflammatory pathways in the placenta triggered by pathogens is one of the main factors responsible for pregnancy complications. Type I IFNs are key molecules modulating immune responses at the level of the placenta and are crucial for protection of the pregnancy via their antiviral and immune modulatory properties. In this study, we elucidate the mechanisms controlling the basal expression of IFN? and its negative feedback. Using in vitro and in vivo animal models, we found that TLR signaling maintains basal IFN? levels through the TLR4-MyD88-independent TBK/IRF3 signaling pathway. We describe the role of the TAM receptor Axl in the regulation of IFN? function in human and mouse trophoblast cells. The absence of TAM receptors in vivo is associated with fetal demise due to dysregulation of IFN? expression and its pro-apoptotic downstream effectors. Collectively, our data describe a feedback signaling pathway controlling the expression and function of IFN? in the trophoblast that is essential for an effective response during viral and microbial infections.

SUBMITTER: Kwon JY

PROVIDER: S-EPMC6269429 | biostudies-literature | 2018 Dec

REPOSITORIES: biostudies-literature

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Relevance of placental type I interferon beta regulation for pregnancy success.

Kwon Ja-Young JY Aldo Paulomi P You Yuan Y Ding Jiahui J Racicot Karen K Dong Xiaoyan X Murphy John J Glukshtad Guy G Silasi Michelle M Peng Jian J Wen Li L Abrahams Vikki M VM Romero Roberto R Mor Gil G

Cellular & molecular immunology 20180615 12

Pregnancy is a unique immunologic and microbial condition that requires an adequate level of awareness to provide a fast and protective response against pathogens as well as to maintain a state of tolerance to paternal antigens. Dysregulation of inflammatory pathways in the placenta triggered by pathogens is one of the main factors responsible for pregnancy complications. Type I IFNs are key molecules modulating immune responses at the level of the placenta and are crucial for protection of the ...[more]

PMID: 29907882

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Project description:BACKGROUND: During human pregnancy, the placental villi produces high amounts of estradiol. This steroid is secreted by the syncytium, which is directly in contact with maternal blood. Estradiol has to cross placental foetal vessels to reach foetal circulation. The enzyme 17beta-hydroxysteroid dehydrogenase type 2 (17beta-HSD2) was detected in placental endothelial cells of foetal vessels inside the villi. This enzyme catalyzes the conversion of estradiol to estrone, and of testosterone to androstenedione. It was proposed that estradiol level into foetal circulation could be regulated by 17beta-HSD2. METHODS: We obtained placentas from 10 to 26 6/7 weeks of pregnancy from women undergoing voluntary termination of pregnancy, term placentas were collected after normal spontaneous vaginal deliveries. We quantified 17beta-HSD2 mRNA levels in mid-gestation and term human placenta by RT-QPCR. We produced a new anti-17beta-HSD2 antibody to study its spatio-temporal expression by immunohistochemistry. We also compared steroid levels (testosterone, estrone and estradiol) and 17beta-HSD2 mRNA and protein levels between term placenta and endometrium. RESULTS: High 17beta-HSD2 mRNA and protein levels were found in both mid-gestation and term placentas. However, we showed that 17beta-HSD2 mRNA levels increase by 2.27 fold between mid-gestation and term. This period coincides with a transitional phase in the development of the villous vasculature. In mid-gestation placenta, high levels of 17beta-HSD2 were found in mesenchymal villi and immature intermediate villi, more precisely in endothelial cells of the stromal channel. At term, high levels of 17beta-HSD2 were found in the numerous sinusoidal capillaries of terminal villi. 17beta-HSD2 mRNA and protein levels in term placentas were respectively 25.4 fold and 30 to 60 fold higher than in the endometrium. Steroid levels were also significantly higher in term placenta than in the endometrium. CONCLUSION: The spatial and temporal expression of 17beta-HSD2 in the placenta during pregnancy and the comparison of 17beta-HSD2 expression and steroid levels between placental villi and endometrium are compatible with a role in the modulation of active and inactive forms of estrogens. Our observations strongly support the hypothesis that 17beta-HSD2 acts as a barrier decreasing estradiol secretion rates in the foetal circulation.

Dataset Information

Relevance of placental type I interferon beta regulation for pregnancy success.

Publications

Relevance of placental type I interferon beta regulation for pregnancy success.

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