Induction of neutrophil death resembling neither apoptosis nor necrosis byONO-AE-248, a selective agonist for PGE(2) receptor subtype 3

An increase of intracellular cAMP mediated by prostaglandin E-2 (PGE(2)) ha s been shown to delay spontaneous apoptosis of neutrophils. It has been dem onstrated that a selective agonist for PGE(2) receptor subtype 3 (the EP3 r eceptor) is capable of decreasing cAMP and stimulating phosphoinositide tur nover in various types of cells. We investigated the effect of a selective EP3 receptor agonist, ONO-AE-248, on neutrophil viability. ONO-AE-248 rapid ly caused a unique form of neutrophil death. The agonist primarily induced morphological changes of the nucleus, including fusion of the lobules, decr eased compactness of the chromatin, and blebbing and rupture of the nuclear membrane. This was followed by an increase of plasma membrane permeability and cell lysis. During these processes, neither apoptotic changes such as nuclear condensation, DNA fragmentation, and expression of phospholipid pho sphatidylserine on the plasma membrane nor necrotic changes such as chromat in clumping and organelle destruction were apparent in the treated neutroph ils. The fatal effect of the agonist might be specific for neutrophils beca use it failed to promote the rapid death of other types of cells. Although activation of neutrophils by ONO-AE-248 was not evident, experiments using metabolic inhibitors demonstrated that the agonist caused neutrophil death via the activation of protein kinase in the presence of intracellular ATP. These findings indicated that EP3 receptor-mediated signals might promote a novel form of neutrophil death, which differs from typical apoptosis or ne crosis.