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.
Hoshino
Tatsuya
T
Faculty of Pharmaceutical Sciences, Okayama University, Okayama 700-8530, Japan.
Tsutsumi
Shinji
S
Tomisato
Wataru
W
Hwang
Hyun-Jung
HJ
Tsuchiya
Tomofusa
T
Mizushima
Tohru
T
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D020169:Caspases / Q000378:metabolism; D003574:Cytochrome c Group / Q000378:metabolism; D015232:Dinoprostone / Q000494:pharmacology*; D005753:Gastric Mucosa / Q000166:cytology / Q000201:enzymology / Q000502:physiology*; D006168:Guinea Pigs; D007700:Kinetics; D008928:Mitochondria / Q000187:drug effects / Q000502:physiology; D018078:Receptors, Prostaglandin E / Q000819:agonists / Q000187:drug effects / Q000502:physiology*; D058307:Receptors, Prostaglandin E, EP2 Subtype; D058309:Receptors, Prostaglandin E, EP4 Subtype
D003574:Cytochrome c Group; D018078:Receptors, Prostaglandin E; D058307:Receptors, Prostaglandin E, EP2 Subtype; D058309:Receptors, Prostaglandin E, EP4 Subtype; D020169:Caspases; D015232:Dinoprostone