title: Deletion of prostaglandin E2 synthesizing enzymes in brain endothelial cells attenuates inflammatory fever.
abstract: 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.
authors.affiliation: Department of Clinical and Experimental Medicine, Linköping University, 58185 Linköping, Sweden.
authors.forename: Daniel Björk
authors.initials: DB
authors.lastname: Wilhelms
authors.affiliation: Department of Clinical and Experimental Medicine, Linköping University, 58185 Linköping, Sweden.
authors.forename: Milen
authors.initials: M
authors.lastname: Kirilov
authors.affiliation: Department of Clinical and Experimental Medicine, Linköping University, 58185 Linköping, Sweden.
authors.forename: Elahe
authors.initials: E
authors.lastname: Mirrasekhian
authors.affiliation: Department of Clinical and Experimental Medicine, Linköping University, 58185 Linköping, Sweden.
authors.forename: Anna
authors.initials: A
authors.lastname: Eskilsson
authors.affiliation: Department of Clinical and Experimental Medicine, Linköping University, 58185 Linköping, Sweden.
authors.forename: Unn Örtegren
authors.initials: UÖ
authors.lastname: Kugelberg
authors.affiliation: Department of Clinical and Experimental Medicine, Linköping University, 58185 Linköping, Sweden.
authors.forename: Christine
authors.initials: C
authors.lastname: Klar
authors.affiliation: Institute of Experimental and Clinical Pharmacology and Toxicology, University of Lübeck, 23538 Lübeck, Germany, and.
authors.forename: Dirk A
authors.initials: DA
authors.lastname: Ridder
authors.affiliation: Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California, Los Angeles, California 90095-1570.
authors.forename: Harvey R
authors.initials: HR
authors.lastname: Herschman
authors.affiliation: Institute of Experimental and Clinical Pharmacology and Toxicology, University of Lübeck, 23538 Lübeck, Germany, and.
authors.forename: Markus
authors.identifier: http://orcid.org/0000-0002-4510-9718
authors.initials: M
authors.lastname: Schwaninger
authors.affiliation: Department of Clinical and Experimental Medicine, Linköping University, 58185 Linköping, Sweden.
authors.forename: Anders
authors.initials: A
authors.lastname: Blomqvist
authors.affiliation: Department of Clinical and Experimental Medicine, Linköping University, 58185 Linköping, Sweden, david.engblom@liu.se.
authors.forename: David
authors.initials: D
authors.lastname: Engblom
mesh_terms: D000818:Animals; D051546:Cyclooxygenase 2 / Q000378:metabolism; D015232:Dinoprostone / Q000096:biosynthesis*; D042783:Endothelial Cells / Q000378:metabolism*; D004797:Enzyme-Linked Immunosorbent Assay; D005334:Fever / Q000209:etiology / Q000378:metabolism*; D007150:Immunohistochemistry; D007249:Inflammation / Q000150:complications / Q000378:metabolism*; D019746:Intramolecular Oxidoreductases / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016133:Polymerase Chain Reaction; D000071876:Prostaglandin-E Synthases
chemical_list: D051546:Cyclooxygenase 2; D019746:Intramolecular Oxidoreductases; D000071876:Prostaglandin-E Synthases; C000605865:Ptges protein, mouse; D015232:Dinoprostone
keywords: COX-2; PGE2; endothelium; fever; mPGES-1; prostaglandin