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Preeclampsia is associated with reduced ISG15 levels impairing extravillous trophoblast invasion.

ABSTRACT: Preeclampsia (PE), a major cause of excess maternal and perinatal morbidity and mortality, has a worldwide prevalence of 2-8%. Excess inflammation with immune maladaptation in the maternal decidua causes shallow trophoblast invasion, resulting in incomplete spiral artery transformation that are characteristic of PE. To mimic the separate and combined paracrine effects of IL-11 and IL-6 on trophoblasts in normal versus preeclamptic pregnancies, primary cytotrophoblast (CTB) cultures treated with IL-11 or IL-6 or IL-11+IL-6 were analyzed by whole genome microarray. These microarray analyses revealed that IL-11 treated CTBs displayed a total of 283 differentially expressed genes (159 of which are up-regulated and 124 are down-regulated), whereas IL-6 treated CTBs displayed a total of 243 differentially expressed genes (120 are up-regulated and 123 are down-regulated) compared control group. However, IL-11+IL-6 co-treated CTBs exhibited 276 differentially expressed genes (146 of which are up-regulated and 130 are down-regulated) compared to control group. Since IL-11 and IL-6 can compete to activate target cells through binding their shared receptor, the global transcription repertoire of CTB cultures treated with IL-11+IL-6 was compared to those treated with either IL-11 or IL-6. A total of seven genes are differentially regulated by IL-11+IL-6 co-treatment vs. treatment with IL-11 alone (four of which are up-regulated and three down-regulated), whereas compared to IL-6 alone, a total of six genes are differentially regulated by IL-6+IL-11 (all of which are down-regulated). Microarray results of this study support that co-existence of IL-6 and IL-11 impairs the global transcription repertoire of trophoblasts compared to the presence of IL-11 alone, most probably through a mechanism that partial or complete IL-6 binding to gp130 blocks IL-11 action. Importantly, ISG15 is the only commonly affected gene and is downregulated by IL-6 and IL-11 co-treatment compared to control or treatment with either IL-11 or IL-6 alone, suggesting its involvement in PE.

ORGANISM(S): Homo sapiens

PROVIDER: GSE171439 | GEO | 2021/04/04

REPOSITORIES: GEO

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Project description:Preeclampsia (PE), which affects 4-8% of human pregnancies, causes significant maternal and neonatal morbidity and mortality. Within the basal plate, placental cytotrophoblasts (CTBs) of fetal origin invade the uterus and extensively remodel the maternal vasculature. In PE, CTB invasion is often shallow, and vascular remodeling is rudimentary. To better understand possible causes, we conducted a global analysis of gene expression at the maternal-fetal interface in placental samples from women with PE (n = 12; 24-36 wk) vs. samples from women who delivered due to preterm labor with no evidence of infection (n = 11; 24-36 wk), a condition that our previous work showed is associated with normal CTB invasion. Using the HG-U133A&B Affymetrix GeneChip platform, and statistical significance set at log odds-ratio of B >0, 55 genes were differentially expressed in PE. They encoded proteins previously associated with PE [e.g. Flt-1 (vascular endothelial growth factor receptor-1), leptin, CRH, and inhibin] and novel molecules [e.g. sialic acid binding Ig-like lectin 6 (Siglec-6), a potential leptin receptor, and pappalysin-2 (PAPP-A2), a protease that cleaves IGF-binding proteins]. We used quantitative PCR to validate the expression patterns of a subset of the genes. At the protein level, we confirmed PE-related changes in the expression of Siglec-6 and PAPP-A2, which localized to invasive CTBs and syncytiotrophoblasts. Notably, Siglec-6 placental expression is uniquely human, as is spontaneous PE. The functional significance of these novel observations may provide new insights into the pathogenesis of PE, and assaying the circulating levels of these proteins could have clinical utility for predicting and/or diagnosing PE. Keywords: disease state analysis Basal plate biopsies of preterm labor (24-36 weeks; n=11) and preterm severe preeclampsia (24-36 weeeks; n=12) were isolated and the global gene expression profiles determined using Affymetrix Human GeneChips. Comparisons between the preeclampsia samples and the preterm labor controls revealed genes differentially expressed in preeclampsia.

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Preeclampsia is associated with reduced ISG15 levels impairing extravillous trophoblast invasion.

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