Sphingosine-1-phosphate inhibition of trophoblast differentiation through a G(i)-coupled receptor response

The failure of placental trophoblasts to differen- tiate 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) secre- tion and the expression of placental alkaline phosphatase but had no effect on their fusion into multinucleated syncy- tialized cells. G-protein-linked S1P receptors 1, 2, and 3 were found in CTs by reverse transcriptase-polymerase chain re- action, 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 adenyl- ate cyclase and reduced production of intracellular cAMP. This is the first reported effect of S1P on placental tropho- blast function. —Johnstone, E. D., G. Chan, C. P. Sibley, S. T. Davidge, B. Lowen, and L. J. Guilbert. Sphingosine-1-phos- phate inhibition of placental trophoblast differentiation through a G i -coupled receptor response. J. Lipid Res. 2005. 46: 1833-1839.