Cytosolic phospholipase A2alpha regulates induction of brain cyclooxygenase-2 in a mouse model of inflammation

• Published in: American journal of physiology. Regulatory, integrative and comparative physiology Vol. 57; no. 6; p. R1774
• Main Authors: Sapirstein, Adam, Saito, Hideyuki, Texel, Sarah J, Samad, Tarek A
• Format: Journal Article
• Language: English
• Published: Bethesda American Physiological Society 01.06.2005
• Subjects: Brain; Enzymes; Rodents
• ISSN: 0363-6119; 1522-1490

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 A2 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 PGE2 in the brain. These studies seek to determine the function of cytosolic phospholipase A2{alpha} (cPLA2{alpha}) in inflammatory PGE2 production in the brain. We wondered whether cPLA2{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 cPLA2{alpha} (cPLA2{alpha}-/-) after systemic administration of LPS. cPLA2{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 PGE2 concentration of untreated cPLA2{alpha}-/- mice was equal to their wild-type littermates. After LPS treatment, however, the brain concentration of PGE2 was significantly less in cPLA2{alpha}-/- than in cPLA2{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 cPLA2{alpha} regulates COX-2 levels and modulates inflammatory PGE2 levels. These results indicate that cPLA2{alpha} inhibition is a novel anti-inflammatory strategy that modulates, but does not completely prevent, eicosanoid responses. [PUBLICATION ABSTRACT]