Brain endothelial cells are hypothesized to be the major source of prostaglandin E(2) (PGE(2)) responsible for fever because they express 2 PGE(2)-synthesizing enzymes (cyclooxygenase-2 and microsomal-type PGE synthase) in response to pyrogens. To further validate this hypothesis, we examined in rats whether endothelial expression of these enzymes occurs only in the brain, and whether the time course of enzyme expression in brain endothelial cells can explain the time courses of brain PGE(2) level and fever. Intraperitoneal injection of lipopolysaccharide induced these enzymes only in brain endothelial cells, but not in those of peripheral organs including the neck, heart, lung, liver and kidney. Induction of these enzymes in brain endothelial cells was first noticed at 1.5 h after lipopolysaccharide injection, at which time elevation of PGE(2) was also first detected. Fever started just after this time point. These results demonstrate the significance of brain endothelial cells in the PGE(2) production during fever. Unexpectedly, PGE(2) level markedly dropped at 5 h in spite of high levels of these enzymes, implicating the existence of an unknown mechanism that suppresses PGE(2) level during the recovery phase of fever.