4.7 Article

Tumor Necrosis Factor-α Induces a Preeclamptic-like Phenotype in Placental Villi via Sphingosine Kinase 1 Activation

期刊

出版社

MDPI
DOI: 10.3390/ijms23073750

关键词

sphingolipids; inflammatory; sphingosine 1-phosphate; syncytium

资金

  1. Canadian Institutes of Health Research [MOP123488]
  2. Department of Obstetrics and Gynecology
  3. Faculty of Medicine and Dentistry (Medical Science Graduate Program Scholarship, 75th Anniversary Graduate Studentship, Maternal Child and Health Scholarship Program)
  4. Faculty of Graduate Studies and Research at the University of Alberta
  5. Recruitment Scholarship

向作者/读者索取更多资源

This study found that placental SphK1 levels are increased in PE patients, and TNF-alpha induces cell death, shedding, and specific cytokine release through SphK1 activity, affecting syncytial function.
Preeclampsia (PE) involves inadequate placental function. This can occur due to elevated pro-inflammatory tumor necrosis factor-alpha (TNF-alpha). In other tissues, TNF-alpha signals via sphingosine kinase 1 (SphK1). SphK1 hinders syncytial formation. Whether this occurs downstream of TNF-alpha signaling is unclear. We hypothesized that placental SphK1 levels are higher in PE and elevated TNF-alpha 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-alpha 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-alpha 2, IFN-gamma-induced protein 10, fibroblast growth factor 2, and platelet-derived growth factor-AA release induced by TNF-alpha were reversed upon SphK1 inhibition. TNF-alpha increased the release of 26 cytokines independently of SphK1. TNF-alpha decreased IL-10 release and inhibiting SphK1 reversed this effect. Inhibiting SphK1 alone decreased TNF-alpha release. Hence, SphK1 partially mediates the TNF-alpha-induced PE placental phenotype, primarily through cell damage, shedding, and specific cytokine release.

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