Prostaglandin E₂ protects gastric mucosal cells from apoptosis via EP₂ and EP₄ receptor activation

Prostaglandin E₂ (PGE₂) has a strong protective effect on the gastric mucosa in vivo; however, the molecular mechanism of a direct cytoprotective effect of PGE₂ on gastric mucosal cells has yet to be elucidated. Although we reported previously that PGE2 inhibited gastric irritant-induced apoptotic DNA fragmentation in primary cultures of guinea pig gastric mucosal cells, we show here that PGE₂ inhibits the ethanol-dependent release of cytochrome c from mitochondria. Of the four main subtypes of PGE₂ receptors, we also demonstrated, using subtype-specific agonists, that EP₂ and EP₄ receptors are involved in the PGE₂-mediated protection of gastric mucosal cells from ethanol-induced apoptosis. Activation of EP₂ and EP₄ 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 PGE₂-mediated protection of cells from ethanol-induced apoptosis, suggesting that a PKA pathway is mainly responsible for the PGE₂-mediated inhibition of apoptosis. Based on these results, we considered that PGE₂ 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 PGE₂-mediated protection of the gastric mucosa from gastric irritants in vivo.