Cytosolic phospholipase A₂α 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 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 A_2α (cPLA _2α) in inflammatory PGE₂ production in the brain. We wondered whether cPLA_2α 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 _2α (cPLA_2α^-/-) after systemic administration of LPS. cPLA_2α^-/- 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 cPLA_2α^-/- mice was equal to their wild-type littermates. After LPS treatment, however, the brain concentration of PGE₂ was significantly less in cPLA _2α^-/- than in cPLA_2α^+/+ 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_2α regulates COX-2 levels and, modulates inflammatory PGE₂ levels. These results indicate that cPLA_2α inhibition is a novel anti-inflammatory strategy that modulates, but does not completely prevent, eicosanoid responses.