INVOLVEMENT OF CYCLOOXYGENASE-2 IN LPS-INDUCED FEVER AND REGULATION OF ITS MESSENGER-RNA BY LPS IN THE RAT-BRAIN

We previously showed that a febrile dose of lipopolysaccharide (LPS in rats resulted in induction of cyclooxygenase-2 (COX-2) mRNA in brain blood vessels/leptomeninges and telencephalic neurons. To elucidate th e causal link between fever and LPS-induced COX-2 mRNA, we experimenta lly modified one or the other of these parameters and examined their r elation. 1) LPS-induced fever was suppressed by pretreatment with a CO X-2-specific inhibitor. 2) Levels of COX-2 mRNA in the neurons and blo od vessels 2.5 h after LPS administration were even higher in the inhi bitor pretreated rats (afebrile) than in vehicle-pretreated ones (febr ile). 3) After repeated administration of LPS, rats became tolerant to LPS, in which state LPS induced neither fever nor COX-2 mRNA in blood vessels/ leptomeninges. When rats had not completely established LPS tolerance. they showed various degrees of fever that were closely corr elated with the level of COX-2 mRNA in blood vessels but not with that in neurons. 4) Urethan anesthesia reduced basal as well as LPS-induce d COX-2 mRNA in telencephalic neurons, but the rats still responded to LPS with fever and induction of COX-2 mRNA in the blood vessels/lepto meninges. These results suggest that COX-2 induced in brain blood vess els/leptomeninges is involved in the molecular mechanism of LPS-induce d fever.