Lipopolysaccharide injected into the cerebral ventricle evokes fever through induction of cyclooxygenase-2 in brain endothelial cells

Activation of the arachidonic acid cascade is an essential step for the dev elopment of fever during brain inflammation. We investigated the brain site s where this activation takes place by use of a rat mod el of brain inflamm ation. Intracerebroventricular administration of lipopolysaccharide but not of its vehicle evoked fever. The fever was markedly suppressed when the ra ts had been pretreated with a cyclooxygenase-2-specific inhibitor In situ h ybridization and immunohistochemical studies revealed that cyclooxygenase-2 mRNA and its protein were induced by lipopolysaccharide in blood vessels n ear the cerebral ventricles and in those in the subarachnoidal space. Doubl e immunohistochemical staining revealed that these cyclooxygenase-2-positiv e cells were mostly endothelial cells. The time course of fever and that of cyclooxygenase-2 induction in the endothelial cells were in parallel. Cycl ooxygenase-2 mRNA in a certain type of telencephalic neurons was also upreg ulated by the intracerebroventricular administration, but this neuronal res ponse occurred both in vehicle-injected rats and in lipopolysaccharide-inje cted ones to the same extent. Therefore, the neuronal response was not esse ntial to the development of fever. These results suggest that brain endothe lial cells play a crucial role in the development of fever during brain inf lammation by activating their arachidonic acid cascade.