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The Journal of Neuroscience, April 15, 2001, 21(8):2669-2677
Coexpression of Microsomal-Type Prostaglandin E Synthase with Cyclooxygenase-2 in Brain Endothelial Cells of Rats during Endotoxin-Induced Fever
Kanato Yamagata1, Kiyoshi Matsumura2, Wataru Inoue2, Takuma Shiraki2, Kyoko Suzuki1, Shin Yasuda1, Hiroko Sugiura1, Chunyu Cao3, Yasuyoshi Watanabe3, and Shigeo Kobayashi2 1 Department of Neuropharmacology, Tokyo Metropolitan Institute for Neuroscience, Fuchu 183-8526, Japan, 2 Department of Intelligence Science and Technology, Graduate School of Informatics, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan, and 3 Department of Neuroscience, Osaka Bioscience Institute, Suita, Osaka 565-0874, Japan
Fever is triggered by an elevation of prostaglandin E2 (PGE2) in the brain. However, the mechanism of its elevation remains unanswered. We herein cloned the rat glutathione-dependent microsomal prostaglandin E synthase (mPGES), the terminal enzyme for PGE2 biosynthesis, and examined its induction in the rat brain after intraperitoneal injection of pyrogen lipopolysaccharide (LPS). In Northern blot analysis, mPGES mRNA was weakly expressed in the brain under the normal conditions but was markedly induced between 2 and 4 hr after the LPS injection. In situ hybridization study revealed that LPS-induced mPGES mRNA signals were mainly associated with brain blood vessels, especially vein or venular-type ones, in the whole brain area. Immunohistochemical study demonstrated that mPGES-like immunoreactivity was expressed in the perinuclear region of brain endothelial cells, which were identified as von Willebrand factor-positive cells. Furthermore, in the perinuclear region of the endothelial cells, mPGES was colocalized with cyclooxygenase-2 (COX-2), which is the enzyme essential for the production of the mPGES substrate PGH2. Inhibition of cyclooxygenase-2 activity resulted in suppression of both PGE2 level in the CSF and fever (Cao et al., 1997), suggesting that the two enzymes were functionally linked and that this link is essential for fever. These results demonstrate that brain endothelial cells play an essential role in the PGE2 production during fever by expressing COX-2 and mPGES.
Key words: prostaglandin E synthase; cyclooxygenase-2; endothelial cell; fever; prostaglandin E2; brain
Copyright © 2001 Society for Neuroscience 0270-6474/01/2182669-09$05.00/0
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