Sphingosine 1-Phosphate Activates S1PR3 to Induce a Proinflammatory Phenotype in Human Myometrial Cells.

Autor:	Saurabh K; Department of Obstetrics and Gynecology, Center for Reproductive Health Sciences, Washington University in St. Louis, St. Louis, MO 63110, USA., Mbadhi MN; Department of Obstetrics and Gynecology, Center for Reproductive Health Sciences, Washington University in St. Louis, St. Louis, MO 63110, USA., Prifti KK; Department of Obstetrics and Gynecology, Center for Reproductive Health Sciences, Washington University in St. Louis, St. Louis, MO 63110, USA., Martin KT; Department of Obstetrics and Gynecology, Center for Reproductive Health Sciences, Washington University in St. Louis, St. Louis, MO 63110, USA., Frolova AI; Department of Obstetrics and Gynecology, Center for Reproductive Health Sciences, Washington University in St. Louis, St. Louis, MO 63110, USA.
Jazyk:	angličtina
Zdroj:	Endocrinology [Endocrinology] 2023 Apr 17; Vol. 164 (6).
DOI:	10.1210/endocr/bqad066
Abstrakt:	One of the common mechanisms responsible for obstetric complications, affecting millions of women every year, is abnormal uterine contractility. Despite the critical importance of this process for women's health, the mechanisms of uterine contraction regulation remain poorly understood. The initiation of uterine smooth muscle (myometrial) contraction is an inflammatory process, accompanied by upregulation of proinflammatory genes and cytokine release. In this study, we show that sphingolipid metabolism is activated during human labor and that sphingosine 1-phosphate (S1P), the main bioactive sphingolipid, may modify the myometrial proinflammatory phenotype. Our data in both primary and immortalized human myometrial cells show that exogenous S1P induces a proinflammatory gene signature and upregulates the expression of known inflammatory markers of parturition, such as IL8 and COX2. Using expression of IL8 as a readout for S1P activity in myometrial cells, we established that these S1P effects are mediated through the activation of S1P receptor 3 (S1PR3) and downstream activation of ERK1/2 pathways. Inhibition of S1PR3 in human myometrial cells attenuates upregulation of IL8, COX2, and JUNB both at the mRNA and protein levels. Furthermore, activation of S1PR3 with a receptor-specific agonist recapitulated the effects seen after treatment with exogenous S1P. Collectively, these results suggest a signaling pathway activated by S1P in human myometrium during parturition and propose new targets for development of novel therapeutics to alter uterine contractility during management of preterm labor or labor dystocia. (© The Author(s) 2023. Published by Oxford University Press on behalf of the Endocrine Society.)
Databáze:	MEDLINE
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