Cyclooxygenase-2 is induced in brain blood vessels during fever evoked by peripheral or central administration of tumor necrosis factor.
Cyclooxygenase-2 (COX-2) is an inducible type of enzyme that is involved in prostaglandin biosynthesis. In the present study, we examined whether or not COX-2 is involved in fever that is induced by tumor necrosis factor-alpha (TNF-alpha) and, if so, where in the brain COX-2 is induced by this factor. Intraperitoneal (i.p.) injection of TNF-alpha into rats evoked a fever that started 1 h after the TNF injection, peaked 3 h after the injection, and then gradually declined. The fever was suppressed by pretreatment with a COX-2-specific inhibitor. With a time course similar to that of fever, COX-2 mRNA was induced in brain blood vessels. On the other hand, in some of the telencephalic neurons, COX-2 mRNA was constitutively expressed under the normal condition; but its level gradually decreased during the course of fever. Fever was also evoked by an intracerebroventricular (i.c.v.) injection of TNF-alpha. This febrile response was also suppressed by a COX-2 specific inhibitor and was associated with the induction of COX-2 mRNA in the brain blood vessels. On the other hand, the telencephalic neurons did not show consistent change in COX-2 mRNA level after i.c.v. injection of TNF-alpha or saline. COX-2-like immunoreactivity was found in some cells of the brain blood vessels 3 h after the TNF-alpha injection by either i.p. or i.c.v. route. Most of the COX-2-like immunoreactive cells were endothelial cells since COX-2-like immunoreactivity was colocalized with von Willebrand factor, an endothelial cell marker, in the same cells. These results suggest that the brain blood vessels are the major sites where TNF-alpha enhances PG biosynthesis after peripheral as well as after central injection, and provides further evidence supporting the hypothesis that COX-2 induced in the brain blood vessels is involved in fever.
Cao
C
C
Dept. of Neuroscience, Osaka Bioscience Institute, Suita-shi, Osaka 565, Japan.
Matsumura
K
K
Yamagata
K
K
Watanabe
Y
Y
D000818:Animals; D001921:Brain / Q000098:blood supply* / Q000187:drug effects / Q000201:enzymology*; D051546:Cyclooxygenase 2; D005334:Fever / Q000139:chemically induced / Q000201:enzymology*; D007274:Injections, Intraperitoneal; D007276:Injections, Intraventricular; D007527:Isoenzymes / Q000096:biosynthesis*; D008297:Male; D011451:Prostaglandin-Endoperoxide Synthases / Q000096:biosynthesis*; D051381:Rats; D017208:Rats, Wistar; D014409:Tumor Necrosis Factor-alpha / Q000008:administration & dosage*
D007527:Isoenzymes; D014409:Tumor Necrosis Factor-alpha; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases