Group IB secretory phospholipase A2 induces neuronal cell death via apoptosis.
Group IB secretory phospholipase A2 (sPLA2-IB) mediates cell proliferation, cell migration, hormone release and eicosanoid production via its receptor in peripheral tissues. In the CNS, high-affinity binding sites of sPLA2-IB have been documented. However, it remains obscure whether sPLA2-IB causes biologic or pathologic response in the CNS. To this end, we examined effects of sPLA2-IB on neuronal survival in primary cultures of rat cortical neurons. sPLA2-IB induced neuronal cell death in a concentration-dependent manner. This death was a delayed response requiring a latent time for 6 h; sPLA2-IB-induced neuronal cell death was accompanied with apoptotic blebbing, condensed chromatin, and fragmented DNA, exhibiting apoptotic features. Before cell death, sPLA2-IB liberated arachidonic acid (AA) and generated prostaglandin D2 (PGD2) from neurons. PGD2 and its metabolite, Delta12-PGJ2, exhibited neurotoxicity. Inhibitors of sPLA2 and cyclooxygenase-2 (COX-2) significantly suppressed not only AA release, but also PGD2 generation. These inhibitors significantly prevented neurons from sPLA2-IB-induced neuronal cell death. In conclusion, we demonstrate a novel biological response, apoptosis, of sPLA2-IB in the CNS. Furthermore, the present study suggests that PGD2 metabolites, especially Delta12-PGJ2, might mediate sPLA2-IB-induced apoptosis.
Yagami
Tatsurou
T
Discovery Research Laboratories and Developmental Research Laboratories, Shionogi and Co., Ltd, Osaka, Japan. tatsurou.yagami@shionogi.co.jp
Ueda
Keiichi
K
Asakura
Kenji
K
Hayasaki-Kajiwara
Yoko
Y
Nakazato
Hitoshi
H
Sakaeda
Toshiyuki
T
Hata
Satoshi
S
Kuroda
Takayuki
T
Takasu
Nobuo
N
Hori
Yozo
Y
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D016718:Arachidonic Acid / Q000096:biosynthesis; D002219:Carbamates / Q000494:pharmacology; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D053938:DNA Fragmentation; D004305:Dose-Response Relationship, Drug; D015777:Eicosanoids / Q000096:biosynthesis / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D054500:Group IB Phospholipases A2; D007212:Indolizines / Q000494:pharmacology; D009474:Neurons / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism / Q000648:ultrastructure; D009578:Nitrobenzenes / Q000494:pharmacology; D010741:Phospholipases A / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D054467:Phospholipases A2; D015230:Prostaglandin D2 / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013449:Sulfonamides / Q000494:pharmacology; D013997:Time Factors
D002219:Carbamates; D016861:Cyclooxygenase Inhibitors; D015777:Eicosanoids; D004791:Enzyme Inhibitors; D018691:Excitatory Amino Acid Antagonists; D007212:Indolizines; D009578:Nitrobenzenes; D013449:Sulfonamides; C119389:indoxam; C080955:N-(2-cyclohexyloxy-4-nitrophenyl)methanesulfonamide; D016718:Arachidonic Acid; D010741:Phospholipases A; D054500:Group IB Phospholipases A2; D054467:Phospholipases A2; C516204:Pla2g1b protein, rat; D015230:Prostaglandin D2