TAK1 in brain endothelial cells mediates fever and lethargy
DA Ridder, MF Lang, S Salinin, JP Röderer… - Journal of Experimental …, 2011 - rupress.org
DA Ridder, MF Lang, S Salinin, JP Röderer, M Struss, C Maser-Gluth, M Schwaninger
Journal of Experimental Medicine, 2011•rupress.orgSystemic 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 …
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 …
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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