Modulation of lipid and protein mediators of inflammation by cytosolic phospholipase A2alpha during experimental sepsis.
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.
Uozumi
Naonori
N
Department of Biochemistry and Molecular Biology, Faculty of Medicine, University of Tokyo, Tokyo, Japan.
Kita
Yoshihiro
Y
Shimizu
Takao
T
D000818:Animals; D016207:Cytokines / Q000096:biosynthesis; D004195:Disease Models, Animal; D015777:Eicosanoids / Q000096:biosynthesis; D054513:Group IV Phospholipases A2 / Q000172:deficiency / Q000502:physiology*; D007249:Inflammation / Q000276:immunology*; D008055:Lipids / Q000276:immunology*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D010641:Phenotype; D011506:Proteins / Q000276:immunology*; D018805:Sepsis / Q000201:enzymology* / Q000276:immunology*; D015996:Survival Rate
D016207:Cytokines; D015777:Eicosanoids; D008055:Lipids; D011506:Proteins; D054513:Group IV Phospholipases A2