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Preeclampsia is Associated With Reduced ISG15 Levels Impairing Extravillous Trophoblast Invasion.

ABSTRACT: Among several interleukin (IL)-6 family members, only IL-6 and IL-11 require a gp130 protein homodimer for intracellular signaling due to lack of intracellular signaling domain in the IL-6 receptor (IL-6R) and IL-11R. We previously reported enhanced decidual IL-6 and IL-11 levels at the maternal-fetal interface with significantly higher peri-membranous IL-6 immunostaining in adjacent interstitial trophoblasts in preeclampsia (PE) vs. gestational age (GA)-matched controls. This led us to hypothesize that competitive binding of these cytokines to the gp130 impairs extravillous trophoblast (EVT) differentiation, proliferation and/or invasion. Using global microarray analysis, the current study identified inhibition of interferon-stimulated gene 15 (ISG15) as the only gene affected by both IL-6 plus IL-11 vs. control or IL-6 or IL-11 treatment of primary human cytotrophoblast cultures. ISG15 immunostaining was specific to EVTs among other trophoblast types in the first and third trimester placental specimens, and significantly lower ISG15 levels were observed in EVT from PE vs. GA-matched control placentae (p = 0.006). Induction of primary trophoblastic stem cell cultures toward EVT linage increased ISG15 mRNA levels by 7.8-fold (p = 0.004). ISG15 silencing in HTR8/SVneo cultures, a first trimester EVT cell line, inhibited invasion, proliferation, expression of ITGB1 (a cell migration receptor) and filamentous actin while increasing expression of ITGB4 (a receptor for hemi-desmosomal adhesion). Moreover, ISG15 silencing further enhanced levels of IL-1β-induced pro-inflammatory cytokines (CXCL8, IL-6 and CCL2) in HTR8/SVneo cells. Collectively, these results indicate that ISG15 acts as a critical regulator of EVT morphology and function and that diminished ISG15 expression is associated with PE, potentially mediating reduced interstitial trophoblast invasion and enhancing local inflammation at the maternal-fetal interface. Thus, agents inducing ISG15 expression may provide a novel therapeutic approach in PE.

SUBMITTER: Ozmen A

PROVIDER: S-EPMC9274133 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description: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.

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Preeclampsia is Associated With Reduced ISG15 Levels Impairing Extravillous Trophoblast Invasion.

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