Sphingosine-1 phosphate promotes intestinal epithelial cell proliferation via S1PR2

Sphingosine-1 phosphate (S1P) is a potent bioactive lipid mediator that acts both as an intracellular signaling molecule and a natural ligand of five different G protein-coupled receptors (GPCRs), S1PR1-5. The level of S1P in intestinal tissue is abundant. Previous studies have reported that S1P protects intestinal epithelial cell from apoptosis by activating the ERK and Akt signaling pathways. However, the effect of S1P on intestinal epithelial cell proliferation under physiological conditions and the underlying signaling mechanisms remain to be elucidated. Here, we show that, except for S1PR4, all S1PRs are expressed in normal intestinal epithelial cells with S1PR2 being the most abundant. S1P dose-dependently stimulated cell migration and proliferation, which were inhibited by JTE-013, a selective chemical antagonist of S1PR2, and by a S1PR2 shRNA. S1P significantly upregulated the expression of c-Myc, cyclin D1, E-cadherin and zona occluden-1 (ZO-1), which was completely inhibited by downregulation of S1PR2 expression with a shRNA. In total, the results suggest that S1P-mediated activation of the S1PR2 plays an important role in regulating intestinal epithelial cell proliferation and migration.