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Immune-Induced Fever Is Dependent on Local But Not Generalized Prostaglandin E-2 Synthesis in the Brain
Linköping University, Department of Clinical and Experimental Medicine, Divison of Neurobiology. Linköping University, Faculty of Medicine and Health Sciences.
Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Medicine and Health Sciences.
Linköping University, Department of Clinical and Experimental Medicine, Divison of Neurobiology. Linköping University, Faculty of Medicine and Health Sciences.
Linköping University, Department of Clinical and Experimental Medicine, Center for Social and Affective Neuroscience. Linköping University, Faculty of Medicine and Health Sciences.ORCID iD: 0000-0003-2245-3396
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2017 (English)In: Journal of Neuroscience, ISSN 0270-6474, E-ISSN 1529-2401, Vol. 37, no 19, 5035-5044 p.Article in journal (Refereed) Published
Abstract [en]

Fever occurs upon binding of prostaglandin E-2 (PGE(2)) to EP3 receptors in the median preoptic nucleus of the hypothalamus, but the origin of the pyrogenic PGE(2) has not been clearly determined. Here, using mice of both sexes, we examined the role of local versus generalized PGE(2) production in the brain for the febrile response. In wild-type mice and in mice with genetic deletion of the prostaglandin synthesizing enzyme cyclooxygenase-2 in the brain endothelium, generated with an inducible CreER(T2) under the Slco1c1 promoter, PGE(2) levels in the CSF were only weakly related to the magnitude of the febrile response, whereas the PGE(2) synthesizing capacity in the hypothalamus, as reflected in the levels of cyclooxygenase-2 mRNA, showed strong correlation with the immune-induced fever. Histological analysis showed that the deletion of cyclooxygenase-2 in brain endothelial cells occurred preferentially in small-and medium-sized vessels deep in the brain parenchyma, such as in the hypothalamus, whereas larger vessels, and particularly those close to the neocortical surface and in the meninges, were left unaffected, hence leaving PGE(2) synthesis largely intact in major parts of the brain while significantly reducing it in the region critical for the febrile response. Furthermore, injection of a virus vector expressing microsomal prostaglandin E synthase-1 (mPGES-1) into the median preoptic nucleus of fever-refractive mPGES-1 knock-out mice, resulted in a temperature elevation in response to LPS. We conclude that the febrile response is dependent on local release of PGE(2) onto its target neurons and not on the overall PGE(2) production in the brain.

Place, publisher, year, edition, pages
SOC NEUROSCIENCE , 2017. Vol. 37, no 19, 5035-5044 p.
Keyword [en]
cyclooxygenase-2; endothelial cells; fever; median preoptic nucleus; microsomal prostaglandin E synthase-1; prostaglandin E2
National Category
Neurosciences
Identifiers
URN: urn:nbn:se:liu:diva-138257DOI: 10.1523/JNEUROSCI.3846-16.2017ISI: 000401118600015PubMedID: 28438967OAI: oai:DiVA.org:liu-138257DiVA: diva2:1109125
Note

Funding Agencies|Swedish Medical Research Council; Swedish Cancer Foundation; European Research Council; Knut and Alice Wallenberg Foundation; Swedish Brain foundation; County Council of Ostergotland

Available from: 2017-06-13 Created: 2017-06-13 Last updated: 2017-06-13

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Eskilsson, AnnaMatsuwaki, TakashiShionoya, KisekoMirrasekhian, ElaheZajdel, JoannaEngblom, DavidBlomqvist, Anders
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Divison of NeurobiologyFaculty of Medicine and Health SciencesDepartment of Clinical and Experimental MedicineCenter for Social and Affective Neuroscience
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CiteExportLink to record
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Citation style
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