title: TAK1 in brain endothelial cells mediates fever and lethargy.
abstract: Systemic inflammation affects the brain, resulting in fever, anorexia, lethargy, and activation of the hypothalamus-pituitary-adrenal axis. How peripheral inflammatory signals reach the brain is still a matter of debate. One possibility is that, in response to inflammatory stimuli, brain endothelial cells in proximity to the thermoregulatory centers produce cyclooxygenase 2 (COX-2) and release prostaglandin E2, causing fever and sickness behavior. We show that expression of the MAP kinase kinase kinase TAK1 in brain endothelial cells is needed for interleukin 1β (IL-1β)-induced COX-2 production. Exploiting the selective expression of the thyroxine transporter Slco1c1 in brain endothelial cells, we generated a mouse line allowing inducible deletion of Tak1 specifically in brain endothelium. Mice lacking the Tak1 gene in brain endothelial cells showed a blunted fever response and reduced lethargy upon intravenous injection of the endogenous pyrogen IL-1β. In conclusion, we demonstrate that TAK1 in brain endothelial cells induces COX-2, most likely by activating p38 MAPK and c-Jun, and is necessary for fever and sickness behavior.
authors.affiliation: Institute of Experimental and Clinical Pharmacology and Toxicology, University of Lübeck, 23562 Lübeck, Germany.
authors.forename: Dirk A
authors.initials: DA
authors.lastname: Ridder
authors.forename: Ming-Fei
authors.initials: MF
authors.lastname: Lang
authors.forename: Sergei
authors.initials: S
authors.lastname: Salinin
authors.forename: Jan-Peter
authors.initials: JP
authors.lastname: Röderer
authors.forename: Marcel
authors.initials: M
authors.lastname: Struss
authors.forename: Christiane
authors.initials: C
authors.lastname: Maser-Gluth
authors.forename: Markus
authors.initials: M
authors.lastname: Schwaninger
mesh_terms: D000818:Animals; D001921:Brain / Q000201:enzymology*; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism; D015232:Dinoprostone / Q000096:biosynthesis / Q000235:genetics; D042783:Endothelial Cells / Q000201:enzymology*; D005334:Fever / Q000139:chemically induced / Q000201:enzymology* / Q000235:genetics; D016758:Genes, jun / Q000235:genetics; D053583:Interleukin-1beta / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology; D053609:Lethargy / Q000139:chemically induced / Q000201:enzymology* / Q000235:genetics; D020930:MAP Kinase Kinase Kinases / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism; D000099151:MAP Kinase Kinase Kinase 7
chemical_list: D051546:Cyclooxygenase 2; D015232:Dinoprostone; D053583:Interleukin-1beta; D020930:MAP Kinase Kinase Kinases; D009419:Nerve Tissue Proteins; D048051:p38 Mitogen-Activated Protein Kinases; D000099151:MAP Kinase Kinase Kinase 7; C077623:Ptgs2 protein, mouse