Department of Pharmacology and Toxicology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, the Netherlands; Centre for Safety of Substances and Products, National Institute for Public Health and the Environment, Bilthoven, the Netherlands.
Department of Pharmacology and Toxicology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, the Netherlands.
Toxicol In Vitro. 2022 Apr;80:105327. doi: 10.1016/j.tiv.2022.105327. Epub 2022 Feb 5.
Tumor necrosis factor (TNF) regulates trophoblast turnover during the formation of the placental syncytium and can be a potentially relevant target for adverse effects of xenobiotics. We mimicked syncytialization in vitro by stimulating BeWo cells with 50 μM forskolin. Undifferentiated and syncytialized BeWo cells were exposed to TNF (10 pg/mL-10 ng/mL) for 48 h after which cell viability, progesterone release and gene expression of a selected set of markers representative for placental function were assessed. In undifferentiated BeWo cells, high TNF levels (1-10 ng/mL) increased gene expression of TNF, NF-κB, and TNFRSF1B to maximally 99 ± 17, 2.2 ± 0.2, and 3.0 ± 0.4 of control values, respectively (p < 0.001). These effects were also found in syncytialized BeWo cells but less pronounced. Additionally, TNF may induce syncytialization in BeWo cells as it upregulated ERVW-1 expression by 1.55 ± 0.14-fold (p < 0.05). On the contrary, TNF levels of 10 and 100 pg/mL did not affect gene expression in both undifferentiated and syncytialized BeWo cells, but did enhance cell viability in syncytialised BeWo cells (p < 0.001). In conclusion, we found that high TNF levels (1-10 ng/mL) increased gene expression of TNF, NF-κB, and TNFRSF1B especially in undifferentiated BeWo cells, while physiological TNF concentrations positively affected cell viability and while there was no effect on any of the investigated functional markers.
肿瘤坏死因子 (TNF) 调节胎盘合体滋养层细胞的更替，在胎盘合体化的形成过程中，它可能成为外来物质产生不良反应的潜在靶点。我们通过用 50 μM 佛司可林刺激 BeWo 细胞来模拟合体化。在分化和合体化的 BeWo 细胞中，在 48 小时内用 TNF（10 pg/mL-10 ng/mL）处理细胞，然后评估细胞活力、孕激素释放和一组代表胎盘功能的标记物的基因表达。在未分化的 BeWo 细胞中，高浓度的 TNF（1-10 ng/mL）将 TNF、NF-κB 和 TNFRSF1B 的基因表达分别增加到对照值的最大值 99±17、2.2±0.2 和 3.0±0.4（p<0.001）。在合体化的 BeWo 细胞中也发现了这些作用，但程度较轻。此外，TNF 可能通过上调 ERVW-1 的表达来诱导 BeWo 细胞的合体化，其表达水平增加了 1.55±0.14 倍（p<0.05）。相反，10 和 100 pg/mL 的 TNF 水平对未分化和合体化的 BeWo 细胞的基因表达没有影响，但增强了合体化的 BeWo 细胞的活力（p<0.001）。总之，我们发现高浓度的 TNF（1-10 ng/mL）特别在未分化的 BeWo 细胞中增加了 TNF、NF-κB 和 TNFRSF1B 的基因表达，而生理浓度的 TNF 则对细胞活力产生积极影响，而对任何所研究的功能标记物都没有影响。
