Cytosolic phospholipase A2alpha regulates induction of brain cyclooxygenase-2 in a mouse model of inflammation.
The products of arachidonic acid metabolism are key mediators of inflammatory responses in the central nervous system, and yet we do not know the mechanisms of their regulation. The phospholipase A(2) enzymes are sources of cellular arachidonic acid, and the enzymes cyclooxygenase-2 (COX-2) and microsomal PGE synthase-1 (mPGES-1) are essential for the synthesis of inflammatory PGE(2) in the brain. These studies seek to determine the function of cytosolic phospholipase A(2)alpha (cPLA(2)alpha) in inflammatory PGE(2) production in the brain. We wondered whether cPLA(2)alpha functions in inflammation to produce arachidonic acid or to modulate levels of COX-2 or mPGES-1. We investigated these questions in the brains of wild-type mice and mice deficient in cPLA(2)alpha (cPLA(2)alpha(-/-)) after systemic administration of LPS. cPLA(2)alpha(-/-) mice had significantly less brain COX-2 mRNA and protein expression in response to LPS than wild-type mice. The reduction in COX-2 was most apparent in the cells of the cerebral blood vessels and the leptomeninges. The brain PGE(2) concentration of untreated cPLA(2)alpha(-/-) mice was equal to their wild-type littermates. After LPS treatment, however, the brain concentration of PGE(2) was significantly less in cPLA(2)alpha(-/-) than in cPLA(2)alpha(+/+) mice (24.4 +/- 3.8 vs. 49.3 +/- 11.6 ng/g). In contrast to COX-2, mPGES-1 RNA levels increased equally in both mouse genotypes, and mPGES-1 protein was unaltered 6 h after LPS. We conclude that cPLA(2)alpha regulates COX-2 levels and modulates inflammatory PGE(2) levels. These results indicate that cPLA(2)alpha inhibition is a novel anti-inflammatory strategy that modulates, but does not completely prevent, eicosanoid responses.
Sapirstein
Adam
A
Anesthesiology and Critical Care Medicine, Johns Hopkins School of Medicine, 600 N. Wolfe St./Meyer 297-A, Baltimore, MD 21287-7294, USA. Asapirs1@jhmi.edu
Saito
Hideyuki
H
Texel
Sarah J
SJ
Samad
Tarek A
TA
O'Leary
Eileen
E
Bonventre
Joseph V
JV
D000818:Animals; D015153:Blotting, Western; D001921:Brain / Q000201:enzymology*; D051546:Cyclooxygenase 2; D003600:Cytosol / Q000201:enzymology*; D015342:DNA Probes; D015232:Dinoprostone / Q000378:metabolism; D004790:Enzyme Induction / Q000502:physiology; D005260:Female; D005455:Fluorescent Antibody Technique; D015971:Gene Expression Regulation, Enzymologic / Q000502:physiology*; D054513:Group IV Phospholipases A2; D017403:In Situ Hybridization; D007249:Inflammation / Q000201:enzymology*; D008070:Lipopolysaccharides / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010741:Phospholipases A / Q000502:physiology*; D011451:Prostaglandin-Endoperoxide Synthases / Q000096:biosynthesis*; D020133:Reverse Transcriptase Polymerase Chain Reaction
D015342:DNA Probes; D008070:Lipopolysaccharides; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; D010741:Phospholipases A; D054513:Group IV Phospholipases A2; D015232:Dinoprostone