Prostaglandin E2 induces apoptosis in cultured rat microglia.
Prostaglandin E2 (PGE2) plays a critical role in the modulation of microglial function including migration and phagocytosis through EP2, which increases intracellular cyclic adenosine monophosphate (AMP) concentration. In the present study, we found that PGE2 reduces cell viability in microglia. PGE2 decreased 3-(4,5-dimethylthiazol-2-thiazolyl)-2,5-diphenyltetrazolium bromide (MTT) reduction and increased lactate dehydrogenase release, deoxyribonucleic acid fragmentation, and poly(ADP-ribose) polymerase cleavage after 24h incubation, suggesting that PGE2 induces apoptosis in these cells. An EP2 agonist, butaprost, and an EP4 agonist, PGE1 alcohol, also induced apoptosis, while an EP1 agonist, 17-phenyl trinor PGE2, or an EP3 agonist, sulprostone, at 10(-6)M did not. On the other hand, EP1-EP4 antagonists, SC-51322, AH6809, L-798106, or GW627368X, up to 10(-5)M did not affect the decrease in MTT reduction by PGE2. Intracellular cyclic AMP accumulation was induced by butaprost, but not 17-phenyl trinor PGE2, sulprostone, or PGE1 alcohol at 10(-6)M. Additionally, we previously reported that PGE2-induced intracellular cyclic AMP accumulation was reversed by AH6809. Besides EP receptors, one of other targets was thought to be prostaglandin transporter, but its inhibitors, bromocresol green or U-46619 up to 10(-5)M did not affect the decrease in MTT reduction by PGE2. These results suggest that PGE2 induces apoptosis in microglia independent of intracellular cyclic AMP concentration, and there are different mechanisms between PGE2-induced apoptosis and the modulation of microglial function.
Department of Pharmacology, Hyogo College of Medicine, 1-1 Mukogawa-cho, Nishinomiya, Hyogo 663-8501, Japan.
Takayuki
T
Nagano
Department of Pharmacology, Hyogo College of Medicine, 1-1 Mukogawa-cho, Nishinomiya, Hyogo 663-8501, Japan.
Shinya H
SH
Kimura
Department of Pharmacology, Hyogo College of Medicine, 1-1 Mukogawa-cho, Nishinomiya, Hyogo 663-8501, Japan. Electronic address: m-takemu@hyo-med.ac.jp.
Motohiko
M
Takemura
D000527:Alprostadil / Q000031:analogs & derivatives / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D015153:Blotting, Western; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000378:metabolism; D053938:DNA Fragmentation; D015232:Dinoprostone / Q000378:metabolism*; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D017628:Microglia / Q000502:physiology*; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D017208:Rats, Wistar; D058306:Receptors, Prostaglandin E, EP1 Subtype / Q000037:antagonists & inhibitors / Q000378:metabolism; D058307:Receptors, Prostaglandin E, EP2 Subtype / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism; D058308:Receptors, Prostaglandin E, EP3 Subtype / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism; D058309:Receptors, Prostaglandin E, EP4 Subtype / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism
D058306:Receptors, Prostaglandin E, EP1 Subtype; D058307:Receptors, Prostaglandin E, EP2 Subtype; D058308:Receptors, Prostaglandin E, EP3 Subtype; D058309:Receptors, Prostaglandin E, EP4 Subtype; C033246:prostaglandin E3; D000242:Cyclic AMP; D007770:L-Lactate Dehydrogenase; D011065:Poly(ADP-ribose) Polymerases; D000527:Alprostadil; D015232:Dinoprostone
Apoptosis; Cell death; Cyclic AMP; Microglia; Prostaglandin E(2); Transporter