Cyclooxygenase-2 is induced in brain blood vessels during fever evoked by peripheral or central administration of tumor necrosis factor

Brain Res Mol Brain Res. 1998 May;56(1-2):45-56. doi: 10.1016/s0169-328x(98)00025-4.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Brain / blood supply*
  • Brain / drug effects
  • Brain / enzymology*
  • Cyclooxygenase 2
  • Fever / chemically induced
  • Fever / enzymology*
  • Injections, Intraperitoneal
  • Injections, Intraventricular
  • Isoenzymes / biosynthesis*
  • Male
  • Prostaglandin-Endoperoxide Synthases / biosynthesis*
  • Rats
  • Rats, Wistar
  • Tumor Necrosis Factor-alpha / administration & dosage*


  • Isoenzymes
  • Tumor Necrosis Factor-alpha
  • Cyclooxygenase 2
  • Prostaglandin-Endoperoxide Synthases