Cytosolic
phospholipase A(2)alpha (cPLA(2)alpha) is one of the key
enzymes in
lipid mediator generation. It preferentially hydrolyzes arachidonoyl-
phospholipid in response to cellular stimuli, liberating
arachidonic acid, the shared precursor of PGs and
leukotrienes. Mice with disruption of the cPLA(2)alpha gene exhibit a more than 80% decrease in the generation of these
lipid mediators, leading to dramatic phenotypes in various models of inflammatory and allergic disease. In this study, we use the cecal
ligation and
puncture model of
sepsis along with multiplex quantitation systems to explore interactions between
eicosanoids and
protein mediators. cPLA(2)alpha-deficient mice exhibited significantly less
weight loss accompanied by decreased generation of PGs,
leukotriene B(4),
IL-6, and CCL2. Despite these differences, genetic ablation of cPLA(2)alpha did not provide any survival advantage. Unexpectedly, abundant production of 12-hydroxy-eicosatetraenoic
acid, another
arachidonic acid-derived
lipid mediator, was found to be unaffected by disruption of the cPLA(2)alpha gene.
Eicosanoid production preceded the production of
cytokines.
Eicosanoid modulation of
IL-6 and CCL2 expression was suggested by scattergram analyses. These results provide in vivo evidence for the rapid generation of
eicosanoids, regulatory role(s) for cPLA(2)alpha-derived
lipid mediators on
protein mediator production, and the existence of a robust cPLA(2)alpha-independent pathway(s) of
eicosanoid generation.