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TAK1 in brain endothelial cells mediates fever and lethargy

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...

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Autores principales: Ridder, Dirk A., Lang, Ming-Fei, Salinin, Sergei, Röderer, Jan-Peter, Struss, Marcel, Maser-Gluth, Christiane, Schwaninger, Markus
Formato: Online Artículo Texto
Lenguaje:English
Publicado: The Rockefeller University Press 2011
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3244031/
https://www.ncbi.nlm.nih.gov/pubmed/22143887
http://dx.doi.org/10.1084/jem.20110398
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author Ridder, Dirk A.
Lang, Ming-Fei
Salinin, Sergei
Röderer, Jan-Peter
Struss, Marcel
Maser-Gluth, Christiane
Schwaninger, Markus
author_facet Ridder, Dirk A.
Lang, Ming-Fei
Salinin, Sergei
Röderer, Jan-Peter
Struss, Marcel
Maser-Gluth, Christiane
Schwaninger, Markus
author_sort Ridder, Dirk A.
collection PubMed
description 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.
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spelling pubmed-32440312012-06-19 TAK1 in brain endothelial cells mediates fever and lethargy Ridder, Dirk A. Lang, Ming-Fei Salinin, Sergei Röderer, Jan-Peter Struss, Marcel Maser-Gluth, Christiane Schwaninger, Markus J Exp Med Brief Definitive Report 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. The Rockefeller University Press 2011-12-19 /pmc/articles/PMC3244031/ /pubmed/22143887 http://dx.doi.org/10.1084/jem.20110398 Text en © 2011 Ridder et al. This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/).
spellingShingle Brief Definitive Report
Ridder, Dirk A.
Lang, Ming-Fei
Salinin, Sergei
Röderer, Jan-Peter
Struss, Marcel
Maser-Gluth, Christiane
Schwaninger, Markus
TAK1 in brain endothelial cells mediates fever and lethargy
title TAK1 in brain endothelial cells mediates fever and lethargy
title_full TAK1 in brain endothelial cells mediates fever and lethargy
title_fullStr TAK1 in brain endothelial cells mediates fever and lethargy
title_full_unstemmed TAK1 in brain endothelial cells mediates fever and lethargy
title_short TAK1 in brain endothelial cells mediates fever and lethargy
title_sort tak1 in brain endothelial cells mediates fever and lethargy
topic Brief Definitive Report
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3244031/
https://www.ncbi.nlm.nih.gov/pubmed/22143887
http://dx.doi.org/10.1084/jem.20110398
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