Coexpression of microsomal-type prostaglandin E synthase with cyclooxygenase-2 in brain endothelial cells of rats during endotoxin-induced fever

Fever is triggered by an elevation of prostaglandin E-2 (PGE(2)) in the bra in. However, the mechanism of its elevation remains unanswered. We herein c loned the rat glutathione-dependent microsomal prostaglandin E synthase (mP GES), the terminal enzyme for PGE(2) biosynthesis, and examined its inducti on in the rat brain after intraperitoneal injection of pyrogen lipopolysacc haride (LPS). In Northern blot analysis, mPGES mRNA was weakly expressed in the brain under the normal conditions but was markedly induced between 2 a nd 4 hr after the LPS injection. In situ hybridization study revealed that LPS-induced mPGES mRNA signals were mainly associated with brain blood vess els, especially vein or venular-type ones, in the whole brain area. Immunoh istochemical study demonstrated that mPGES-like immunoreactivity was expres sed in the perinuclear region of brain endothelial cells, which were identi fied as von Willebrand factor-positive cells. Furthermore, in the perinucle ar region of the endothelial cells, mPGES was colocalized with cyclooxygena se-2 (COX-2), which is the enzyme essential for the production of the mPGES substrate PGH(2). Inhibition of cyclooxygenase-2 activity resulted in supp ression of both PGE(2) level in the CSF and fever (Cao et at., 1997), sugge sting that the two enzymes were functionally linked and that this link is e ssential for fever. These results demonstrate that brain endothelial cells play an essential role in the PGE(2) production during fever by expressing COX-2 and mPGES.