Abstract
The failure of placental trophoblasts to differentiate properly is thought to play an important role in the cause of pregnancy disorders such as preeclampsia. We looked at the effects of the bioactive lipid sphingosine-1-phosphate (S1P) on the differentiation of primary human cytotrophoblasts (CTs) into syncytiotrophoblasts (STs) in culture. We found that S1P inhibited CT differentiation measured by human chorionic gonadotropin (hCG) secretion and the expression of placental alkaline phosphatase but had no effect on their fusion into multinucleated syncytialized cells. G-protein-linked S1P receptors 1, 2, and 3 were found in CTs by reverse transcriptase-polymerase chain reaction, and receptor 1 was found by Western blot analysis. Disruption of G(i) signaling with pertussis toxin reversed the inhibitory effects of S1P. S1P reduced intracellular cAMP, and the addition of 8-bromo-cAMP reversed S1P inhibition of hCG secretion. Therefore, we suggest that S1P inhibits the differentiation of CTs into STs through G(i)-coupled S1P receptor interaction(s), leading to the inhibition of adenylate cyclase and reduced production of intracellular cAMP. This is the first reported effect of S1P on placental trophoblast function.
Highlights
The failure of placental trophoblasts to differentiate properly is thought to play an important role in the cause of pregnancy disorders such as preeclampsia
Each receptor signals to multiple downstream responses by coupling to different G-proteins: S1P1 exclusively links to Gi, S1P2 and S1P3 link to Gi, Gq, and G12/13, and S1P4 and S1P5 link to Gi and Gq
We show that S1P inhibits the functional markers of differentiation (PLAP and human chorionic gonadotropin (hCG)), but not fusion, in a 5 day culture with epidermal growth factor (EGF)
Summary
The failure of placental trophoblasts to differentiate properly is thought to play an important role in the cause of pregnancy disorders such as preeclampsia. We suggest that S1P inhibits the differentiation of CTs into STs through Gi-coupled S1P receptor interaction(s), leading to the inhibition of adenylate cyclase and reduced production of intracellular cAMP. This is the first reported effect of S1P on placental trophoblast function.—Johnstone, E. Sphingosine-1-phosphate (S1P) is a member of an important group of signaling sphingolipids recognized to play a role in a diverse array of cellular processes, such as apoptosis, cell motility, calcium signaling, differentiation, and proliferation [1]. A role was proposed in cell differentiation [10]
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