期刊
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
卷 23, 期 7, 页码 -出版社
MDPI
DOI: 10.3390/ijms23073750
关键词
sphingolipids; inflammatory; sphingosine 1-phosphate; syncytium
资金
- Canadian Institutes of Health Research [MOP123488]
- Department of Obstetrics and Gynecology
- Faculty of Medicine and Dentistry (Medical Science Graduate Program Scholarship, 75th Anniversary Graduate Studentship, Maternal Child and Health Scholarship Program)
- Faculty of Graduate Studies and Research at the University of Alberta
- Recruitment Scholarship
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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