Prostaglandin E2 Protects Gastric Mucosal Cells from Apoptosis via EP2 and EP4 Receptor Activation

Prostaglandin E 2 (PGE 2 ) has a strong protective effect on the gastric mucosa in vivo ; however, the molecular mechanism of a direct cytoprotective effect of PGE 2 on gastric mucosal cells has yet to be elucidated. Although we reported previously that PGE 2 inhibited gastric irritant-induced apoptotic DNA fragmentation in primary cultures of guinea pig gastric mucosal cells, we show here that PGE 2 inhibits the ethanol-dependent release of cytochrome c from mitochondria. Of the four main subtypes of PGE 2 receptors, we also demonstrated, using subtype-specific agonists, that EP 2 and EP 4 receptors are involved in the PGE 2 -mediated protection of gastric mucosal cells from ethanol-induced apoptosis. Activation of EP 2 and EP 4 receptors is coupled with an increase in cAMP, for which a cAMP analogue was found here to inhibit the ethanol-induced apoptosis. The increase in cAMP is known to activate both protein kinase A (PKA) and phosphatidylinositol 3-kinase pathways. An inhibitor of PKA but not of phosphatidylinositol 3-kinase blocked the PGE 2 -mediated protection of cells from ethanol-induced apoptosis, suggesting that a PKA pathway is mainly responsible for the PGE 2 -mediated inhibition of apoptosis. Based on these results, we considered that PGE 2 inhibited gastric irritant-induced apoptosis in gastric mucosal cells via induction of an increase in cAMP and activation of PKA, and that this effect was involved in the PGE 2 -mediated protection of the gastric mucosa from gastric irritants in vivo .