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The pro-inflammatory cytokines IFN-α and TNF-α inhibit extravillous trophoblast invasion

ABSTRACT: Impaired trophoblast differentiation and invasion are a hallmark of severe pregnancy complications such as preeclampsia and fetal growth restriction. Women with immune-mediated inflammatory diseases, in particular systemic lupus erythematosus (SLE), have an increased risk for adverse pregnancy outcomes. These diseases are characterized by high activity of pro-inflammatory cytokines, such as interferon alpha (IFN-α) and tumor necrosis factor alpha (TNF-α). Here, we investigated the direct effects of these cytokines on extravillous trophoblast (EVT) differentiation and invasion, using trophoblast stem cells (TSCs), trophoblast organoids, and first-trimester placental and decidual tissue. While neither cytokine impaired EVT differentiation, both significantly reduced EVT invasion into extracellular matrix and/or maternal decidua. Transcriptomic analysis revealed cytokine-induced alterations in gene expression associated with epithelial-mesenchymal transition (EMT), a key process in EVT invasion. These findings suggest that elevated IFN-α and TNF-α levels may directly impair placental development by inhibiting EVT invasion, providing a mechanistic link between inflammatory conditions such SLE and adverse pregnancy outcomes.

ORGANISM(S): Homo sapiens

PROVIDER: GSE302798 | GEO | 2026/05/08

REPOSITORIES: GEO

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Project description:Invasion of cytotrophoblasts into uterine tissues is essential for placental development. To identify molecules regulating trophoblast invasion, mRNA signatures of purified villous (CTB, poor invasiveness) and extravillous (EVT, high invasiveness) trophoblasts isolated from first trimester human placentae and villous explant cultures, respectively, were compared using GeneChip analyses yielding 991 invasion/migration related transcripts. Several genes involved in physiological and pathologic cell invasion, including ADAM-12,-19,-28 as well as Spondin-2, were upregulated in EVT. Pathway prediction analyses identified several functional modules associated with either the invasive or the non-invasive trophoblast phenotype. One of the genes which were downregulated in the invasive mRNA pool, heme oxygenase-1 (HO-1), was selected for functional analyses. Real-time PCR analyses, Western blottting, and immunofluorescene of first trimester placentae and differentiating villous explant cultures demonstrated downregulation of HO-1 in invasive EVT as compared to CTB. Modulation of HO-1 expression in loss-of as well as gain-of function cell models (BeWo and HTR8/SVneo, respectively) demonstrated an inverse relationship of HO-1 expression with trophoblast migration in transwell and wound healing assays. Importantly, HO-1 expression led to an increase in protein levels and activity of the nuclear hormone receptor PPARgamma. Pharmacological inhibition of PPARgamma abrogated the inhibitory effects of HO-1 on trophoblast migration. Collectively, our results demonstrate that gene expression profiling of EVT and CTB can be used to unravel novel regulators of cell invasion. Accordingly, we identify heme oxygenase-1 as a negative regulator of trophoblast motility acting via upregulation of PPARgamma. Experiment Overall Design: To identify genes potentially regulating cell invasion trophoblast cells of early human gestation with distinct invasive properties were profiled. Experiment Overall Design: Distinct gene expression signatures of highly invasive EVT (n = 6) and poorly invasive CTB (n = 5) of different first trimester placentae using Affymetrix U133A GeneChips interrogating >20,000 genes were determined.

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The pro-inflammatory cytokines IFN-α and TNF-α inhibit extravillous trophoblast invasion

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