title: Lipopolysaccharide-induced fever depends on prostaglandin E2 production specifically in brain endothelial cells.
abstract: Immune-induced prostaglandin E2 (PGE2) synthesis is critical for fever and other centrally elicited disease symptoms. The production of PGE2 depends on cyclooxygenase-2 and microsomal prostaglandin E synthase-1 (mPGES-1), but the identity of the cells involved has been a matter of controversy. We generated mice expressing mPGES-1 either in cells of hematopoietic or nonhematopoietic origin. Mice lacking mPGES-1 in hematopoietic cells displayed an intact febrile response to lipopolysaccharide, associated with elevated levels of PGE2 in the cerebrospinal fluid. In contrast, mice that expressed mPGES-1 only in hematopoietic cells, although displaying elevated PGE2 levels in plasma but not in the cerebrospinal fluid, showed no febrile response to lipopolysaccharide, thus pointing to the critical role of brain-derived PGE2 for fever. Immunohistochemical stainings showed that induced cyclooxygenase-2 expression in the brain exclusively occurred in endothelial cells, and quantitative PCR analysis on brain cells isolated by flow cytometry demonstrated that mPGES-1 is induced in endothelial cells and not in vascular wall macrophages. Similar analysis on liver cells showed induced expression in macrophages and not in endothelial cells, pointing at the distinct role for brain endothelial cells in PGE2 synthesis. These results identify the brain endothelial cells as the PGE2-producing cells critical for immune-induced fever.
authors.affiliation: Department of Clinical and Experimental Medicine, Division of Radiation Physics, Faculty of Health Sciences, Linköping University, S-581 85 Linköping, Sweden.
authors.forename: Linda
authors.initials: L
authors.lastname: Engström
authors.forename: Johan
authors.initials: J
authors.lastname: Ruud
authors.forename: Anna
authors.initials: A
authors.lastname: Eskilsson
authors.forename: Anders
authors.initials: A
authors.lastname: Larsson
authors.forename: Ludmila
authors.initials: L
authors.lastname: Mackerlova
authors.forename: Unn
authors.initials: U
authors.lastname: Kugelberg
authors.forename: Hong
authors.initials: H
authors.lastname: Qian
authors.forename: Ana Maria
authors.initials: AM
authors.lastname: Vasilache
authors.forename: Peter
authors.initials: P
authors.lastname: Larsson
authors.forename: David
authors.initials: D
authors.lastname: Engblom
authors.forename: Mikael
authors.initials: M
authors.lastname: Sigvardsson
authors.forename: Jan-Ingvar
authors.initials: JI
authors.lastname: Jönsson
authors.forename: Anders
authors.initials: A
authors.lastname: Blomqvist
mesh_terms: D000818:Animals; D001921:Brain / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*; D015232:Dinoprostone / Q000096:biosynthesis*; D042783:Endothelial Cells / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*; D005334:Fever / Q000139:chemically induced / Q000276:immunology / Q000378:metabolism*; D019746:Intramolecular Oxidoreductases / Q000235:genetics / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D000071876:Prostaglandin-E Synthases
chemical_list: D008070:Lipopolysaccharides; D019746:Intramolecular Oxidoreductases; D000071876:Prostaglandin-E Synthases; C000605865:Ptges protein, mouse; D015232:Dinoprostone