Role of group V phospholipase A2 in zymosan-induced eicosanoid generation and vascular permeability revealed by targeted gene disruption

Conclusions regarding the contribution of low molecular weight secretory phospholipase A(2) (sPLA(2)) enzymes in eicosanoid generation have relied on data obtained from transfected cells or the use of inhibitors that fail to discriminate between individual members of the large family of mammalian sPLA(2) enzymes. To elucidate the role of group V sPLA(2), we used targeted gene disruption to generate mice lacking this enzyme. Zymosan-induced generation of leukotriene C-4 and prostaglandin E-2 was attenuated similar to50% in peritoneal macrophages from group V sPLA(2)-null mice compared with macrophages from wild-type littermates. Furthermore, the early phase of plasma exudation in response to intraperitoneal injection of zymosan and the accompanying in vivo generation of cysteinyl leukotrienes were markedly attenuated in group V sPLA(2)-null mice compared with wild-type controls. These data provide clear evidence of a role for group V sPLA(2) in regulating eicosanoid generation in response to an acute innate stimulus of the immune response both in vitro and in vivo, suggesting a role for this enzyme in innate immunity.