Immune-induced fever is dependent on local but not generalized prostaglandin E₂ synthesis in the brain

Fever occurs upon binding of prostaglandin E₂ (PGE₂) to EP₃ receptors in the median preoptic nucleus of the hypothalamus, but the origin of the pyrogenic PGE₂ has not been clearly determined. Here, using mice of both sexes, we examined the role of local versus generalized PGE₂ production in the brain for the febrile response. In wild-type mice and in mice with genetic deletion of the prostaglandin synthesizing enzyme cyclooxygenase-2 in the brain endothelium, generated with an inducible CreER^T2 under the Slco1c1 promoter, PGE₂ levels in the CSF were only weakly related to the magnitude of the febrile response, whereas the PGE₂ synthesizing capacity in the hypothalamus, as reflected in the levels of cyclooxygenase-2 mRNA, showed strong correlation with the immune-induced fever. Histological analysis showed that the deletion of cyclooxygenase-2 in brain endothelial cells occurred preferentially in small- and mediumsized vessels deep in the brain parenchyma, such as in the hypothalamus, whereas larger vessels, and particularly those close to the neocortical surface and in the meninges, were left unaffected, hence leaving PGE₂ synthesis largely intact in major parts of the brain while significantly reducing it in the region critical for the febrile response. Furthermore, injection of a virus vector expressing microsomal prostaglandin E synthase-1 (mPGES-1) into the median preoptic nucleus of fever-refractive mPGES-1 knock-out mice, resulted in a temperature elevation in response to LPS. We conclude that the febrile response is dependent on local release of PGE₂ onto its target neurons and not on the overall PGE₂ production in the brain.