Deletion of Prostaglandin E2Synthesizing Enzymes in Brain Endothelial Cells Attenuates Inflammatory Fever

Daniel Björk Wilhelms, Milen Kirilov, Elahe Mirrasekhian, Anna Eskilsson, Unn Örtegren Kugelberg, Christine Klar, Dirk A. Ridder, Harvey R. Herschman, Markus Schwaninger, Anders Blomqvist, David Engblom

Fever is a hallmark of inflammatory and infectious diseases. The febrile response is triggered by prostaglandin E2 synthesis mediated by induced expression of the enzymes cyclooxygenase-2 (COX-2) and microsomal prostaglandin E synthase 1 (mPGES-1). The cellular source for pyrogenic PGE2 remains a subject of debate; several hypotheses have been forwarded, including immune cells in the periphery and in the brain, as well as the brain endothelium. Here we generated mice with selective deletion of COX-2 and mPGES1 in brain endothelial cells. These mice displayed strongly attenuated febrile responses to peripheral immune challenge. In contrast, inflammation-induced hypoactivity was unaffected, demonstrating the physiological selectivity of the response to the targeted gene deletions. These findings demonstrate that PGE2 synthesis in brain endothelial cells is critical for inflammation-induced fever.