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(Journal of Leukocyte Biology. 2000;68:187-193.)
© 2000 by Society for Leukocyte Biology

Induction of neutrophil death resembling neither apoptosis nor necrosis by ONO-AE-248, a selective agonist for PGE₂ receptor subtype 3

Jiajia Liu, Tohru Akahoshi, Shixu Jiang^*, Rie Namai, Hidero Kitasato, Hirahito Endo, Toru Kameya^* and Hirobumi Kondo

Departments of Internal Medicine,
^* Pathology, and
Microbiology, Kitasato University School of Medicine, Kitasato, Sagamihara, Kanagawa, Japan

Correspondence: Tohru Akahoshi, M.D., Ph.D., Department of Internal Medicine, 1-15-1 Kitasato, Sagamihara, Kanagawa, 228-8555 Japan. E-mail: akahoshi{at}med.kitasato-u.ac.jp

An increase of intracellular cAMP mediated by prostaglandin E₂ (PGE₂) has been shown to delay spontaneous apoptosis of neutrophils. It has been demonstrated that a selective agonist for PGE₂ receptor subtype 3 (the EP3 receptor) is capable of decreasing cAMP and stimulating phosphoinositide turnover in various types of cells. We investigated the effect of a selective EP3 receptor agonist, ONO-AE-248, on neutrophil viability. ONO-AE-248 rapidly caused a unique form of neutrophil death. The agonist primarily induced morphological changes of the nucleus, including fusion of the lobules, decreased 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 phosphatidylserine on the plasma membrane nor necrotic changes such as chromatin clumping and organelle destruction were apparent in the treated neutrophils. The fatal effect of the agonist might be specific for neutrophils because 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 C 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 necrosis.

Key Words: cell death • inflammation • protein kinase C • cAMP

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