Department of Obstetrics and Gynecology, University of Alberta, Edmonton, AB T5H 3V9, Canada.
Women and Children's Health Research Institute, Edmonton, AB T6G 1C9, Canada.
Int J Mol Sci. 2022 Mar 29;23(7):3750. doi: 10.3390/ijms23073750.
Preeclampsia (PE) involves inadequate placental function. This can occur due to elevated pro-inflammatory tumor necrosis factor-α (TNF-α). In other tissues, TNF-α signals via sphingosine kinase 1 (SphK1). SphK1 hinders syncytial formation. Whether this occurs downstream of TNF-α signaling is unclear. We hypothesized that placental SphK1 levels are higher in PE and elevated TNF-α decreases syncytial function, increases syncytial shedding, and increases cytokine/factor release via SphK1 activity. Term placental biopsies were analyzed for SphK1 using immunofluorescence and qRT-PCR. Term placental explants were treated after 4 days of culture, at the start of syncytial regeneration, with TNF-α and/or SphK1 inhibitors, PF-543. Syncytialization was assessed by measuring fusion and chorionic gonadotropin release. Cell death and shedding were measured by lactate dehydrogenase release and placental alkaline phosphatase-positive shed particles. Forty-two cytokines were measured using multiplex assays. Placental SphK1 was increased in PE. Increased cell death, shedding, interferon-α2, IFN-γ-induced protein 10, fibroblast growth factor 2, and platelet-derived growth factor-AA release induced by TNF-α were reversed upon SphK1 inhibition. TNF-α increased the release of 26 cytokines independently of SphK1. TNF-α decreased IL-10 release and inhibiting SphK1 reversed this effect. Inhibiting SphK1 alone decreased TNF-α release. Hence, SphK1 partially mediates the TNF-α-induced PE placental phenotype, primarily through cell damage, shedding, and specific cytokine release.
子痫前期 (PE) 涉及胎盘功能不全。这可能是由于促炎肿瘤坏死因子-α (TNF-α) 升高引起的。在其他组织中，TNF-α 通过鞘氨醇激酶 1 (SphK1) 发出信号。SphK1 阻碍合胞体的形成。TNF-α 信号是否发生在 SphK1 下游尚不清楚。我们假设 PE 患者胎盘 SphK1 水平较高，TNF-α 升高会降低合胞体功能，增加合胞体脱落，并通过 SphK1 活性增加细胞因子/因子释放。使用免疫荧光和 qRT-PCR 分析胎盘活检标本中的 SphK1。在培养第 4 天开始合胞体再生时，用 TNF-α 和/或 SphK1 抑制剂 PF-543 处理足月胎盘外植体。通过测量融合和绒毛膜促性腺激素释放来评估合胞体化。通过乳酸脱氢酶释放和胎盘碱性磷酸酶阳性脱落颗粒测量细胞死亡和脱落。使用多重分析测定了 42 种细胞因子。PE 胎盘 SphK1 增加。TNF-α 诱导的细胞死亡、脱落、干扰素-α2、IFN-γ 诱导蛋白 10、成纤维细胞生长因子 2 和血小板衍生生长因子-AA 释放增加，SphK1 抑制后逆转。TNF-α 增加了 26 种细胞因子的释放，而与 SphK1 无关。TNF-α 降低了 IL-10 的释放，抑制 SphK1 逆转了这种效应。单独抑制 SphK1 会降低 TNF-α 的释放。因此，SphK1 部分介导了 TNF-α 诱导的 PE 胎盘表型，主要通过细胞损伤、脱落和特定细胞因子的释放。
