Group IB secretory phospholipase A2 induces neuronal cell death via apoptosis

Group IB secretory phospholipase A(2) (sPLA(2)-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 sPLA(2)-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 sPLA(2)-IB on neuronal survival in primary cultures of rat cortical neurons. sPLA(2)-IB induced neuronal cell death in a concentration-dependent manner. This death was a delayed response requiring a latent time for 6 h; sPLA(2)-IB-induced neuronal cell death was accompanied with apoptotic blebbing, condensed chromatin, and fragmented DNA, exhibiting apoptotic features. Before cell death, sPLA(2)-IB liberated arachidonic acid (AA) and generated prostaglandin D-2 (PGD(2)) from neurons. PGD(2) and its metabolite, Delta12-PGJ(2), exhibited neurotoxicity. Inhibitors Of sPLA(2) and cyclooxygenase-2 (COX-2) significantly suppressed not only AA release, but also PGD(2) generation. These inhibitors significantly prevented neurons from sPLA(2)-IB-induced neuronal cell death. In conclusion, we demonstrate a novel biological response, apoptosis, of sPLA(2)-IB in the CNS. Furthermore, the present study suggests that PGD(2) metabolites, especially Delta12-PGJ(2), might mediate sPLA(2)-IB-induced apoptosis.