{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,27]],"date-time":"2026-09-27T12:33:31Z","timestamp":1790512411114,"version":"4.1.0"},"reference-count":82,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2022,3,29]],"date-time":"2022-03-29T00:00:00Z","timestamp":1648512000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000024","name":"Canadian Institutes of Health Research","doi-asserted-by":"publisher","award":["MOP123488"],"award-info":[{"award-number":["MOP123488"]}],"id":[{"id":"10.13039\/501100000024","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Department of Obstetrics and Gynecology, University of Alberta","award":["N\/A"],"award-info":[{"award-number":["N\/A"]}]},{"DOI":"10.13039\/501100019691","name":"Faculty of Medicine and Dentistry, University of Alberta","doi-asserted-by":"publisher","award":["N\/A"],"award-info":[{"award-number":["N\/A"]}],"id":[{"id":"10.13039\/501100019691","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100007201","name":"Faculty of Graduate Studies and Research, University of Alberta","doi-asserted-by":"publisher","award":["N\/A"],"award-info":[{"award-number":["N\/A"]}],"id":[{"id":"10.13039\/501100007201","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Preeclampsia (PE) involves inadequate placental function. This can occur due to elevated pro-inflammatory tumor necrosis factor-\u03b1 (TNF-\u03b1). In other tissues, TNF-\u03b1 signals via sphingosine kinase 1 (SphK1). SphK1 hinders syncytial formation. Whether this occurs downstream of TNF-\u03b1 signaling is unclear. We hypothesized that placental SphK1 levels are higher in PE and elevated TNF-\u03b1 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-\u03b1 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-\u03b12, IFN-\u03b3-induced protein 10, fibroblast growth factor 2, and platelet-derived growth factor-AA release induced by TNF-\u03b1 were reversed upon SphK1 inhibition. TNF-\u03b1 increased the release of 26 cytokines independently of SphK1. TNF-\u03b1 decreased IL-10 release and inhibiting SphK1 reversed this effect. Inhibiting SphK1 alone decreased TNF-\u03b1 release. Hence, SphK1 partially mediates the TNF-\u03b1-induced PE placental phenotype, primarily through cell damage, shedding, and specific cytokine release.<\/jats:p>","DOI":"10.3390\/ijms23073750","type":"journal-article","created":{"date-parts":[[2022,3,29]],"date-time":"2022-03-29T21:44:52Z","timestamp":1648590292000},"page":"3750","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":17,"title":["Tumor Necrosis Factor-\u03b1 Induces a Preeclamptic-like Phenotype in Placental Villi via Sphingosine Kinase 1 Activation"],"prefix":"10.3390","volume":"23","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1479-8765","authenticated-orcid":false,"given":"Yuliya","family":"Fakhr","sequence":"first","affiliation":[{"name":"Department of Obstetrics and Gynecology, University of Alberta, Edmonton, AB T5H 3V9, Canada"},{"name":"Women and Children\u2019s Health Research Institute, Edmonton, AB T6G 1C9, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Saloni","family":"Koshti","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, University of Alberta, Edmonton, AB T5H 3V9, Canada"},{"name":"Women and Children\u2019s Health Research Institute, Edmonton, AB T6G 1C9, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yasaman Bahojb","family":"Habibyan","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, University of Alberta, Edmonton, AB T5H 3V9, Canada"},{"name":"Women and Children\u2019s Health Research Institute, Edmonton, AB T6G 1C9, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kirsten","family":"Webster","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, University of Alberta, Edmonton, AB T5H 3V9, Canada"},{"name":"Women and Children\u2019s Health Research Institute, Edmonton, AB T6G 1C9, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Denise G.","family":"Hemmings","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, University of Alberta, Edmonton, AB T5H 3V9, Canada"},{"name":"Women and Children\u2019s Health Research Institute, Edmonton, AB T6G 1C9, Canada"},{"name":"Department of Microbiology and Immunology, University of Alberta, Edmonton, AB T6G 2E1, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,3,29]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"628","DOI":"10.1097\/AOG.0000000000000696","article-title":"Risk of Fetal Death With Preeclampsia","volume":"125","author":"Harmon","year":"2015","journal-title":"Obstet. 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