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Deletion of Prostaglandin E-2 Synthesizing Enzymes in Brain Endothelial Cells Attenuates Inflammatory Fever
Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Närsjukvården i centrala Östergötland, Akutkliniken.
Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Hälsouniversitetet.
Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Hälsouniversitetet.ORCID-id: 0000-0003-2245-3396
Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Hälsouniversitetet.
Vise andre og tillknytning
2014 (engelsk)Inngår i: Journal of Neuroscience, ISSN 0270-6474, E-ISSN 1529-2401, Vol. 34, nr 35, s. 11684-11690Artikkel i tidsskrift (Fagfellevurdert) Published
Abstract [en]

Fever is a hallmark of inflammatory and infectious diseases. The febrile response is triggered by prostaglandin E-2 synthesis mediated by induced expression of the enzymes cyclooxygenase-2 (COX-2) and microsomal prostaglandin E synthase 1 (mPGES-1). The cellular source for pyrogenic PGE(2) remains a subject of debate; several hypotheses have been forwarded, including immune cells in the periphery and in the brain, as well as the brain endothelium. Here we generated mice with selective deletion of COX-2 and mPGES1 in brain endothelial cells. These mice displayed strongly attenuated febrile responses to peripheral immune challenge. In contrast, inflammation-induced hypoactivity was unaffected, demonstrating the physiological selectivity of the response to the targeted gene deletions. These findings demonstrate that PGE(2) synthesis in brain endothelial cells is critical for inflammation-induced fever.

sted, utgiver, år, opplag, sider
Society for Neuroscience , 2014. Vol. 34, nr 35, s. 11684-11690
Emneord [en]
COX-2; endothelium; fever; mPGES-1; PGE(2); prostaglandin
HSV kategori
Identifikatorer
URN: urn:nbn:se:liu:diva-111281DOI: 10.1523/JNEUROSCI.1838-14.2014ISI: 000341314900017PubMedID: 25164664OAI: oai:DiVA.org:liu-111281DiVA, id: diva2:755384
Merknad

Funding Agencies|Swedish Medical Research Council; Swedish Cancer Foundation; European Research Council; Knut and Alice Wallenberg Foundation; Swedish Brain foundation; County Council of stergotland; Wenner-Gren Fellowship

Tilgjengelig fra: 2014-10-14 Laget: 2014-10-14 Sist oppdatert: 2018-01-11
Inngår i avhandling
1. Fever: Role of brain endothelial prostaglandins
Åpne denne publikasjonen i ny fane eller vindu >>Fever: Role of brain endothelial prostaglandins
2014 (engelsk)Doktoravhandling, med artikler (Annet vitenskapelig)
Abstract [en]

Fever and loss of appetite are two of the most fundamental manifestations of disease. These disease symptoms, which lead to deviations from normal body temperature and food intake patterns, are seen in a vast array of infectious and inflammatory conditions. It is known that peripheral signals from the immune system are essential triggers for these responses, which are orchestrated by neuronal circuits in the brain. Due to the blood‐brain barrier, peripheral inflammatory signals require a specific mode of transmission into the brain. Such mechanisms have been proposed, but interventional studies of these mechanisms have never rendered conclusive results. In this thesis, we present the first functional evidence of cyclooxygenase 2 (COX‐2) and microsomal prostaglandin E synthase type 1 (mPGES‐1) mediated prostaglandin E2 synthesis in the blood‐brain barrier endothelial cells as a signaling mechanism in the initiation of inflammatory fever. We also show that one of the world’s most widely used antipyretics, paracetamol, acts by inhibition of COX‐2. Combined with the finding that COX‐2 and mPGES‐1 in brain endothelial cells play a key role in inflammatory fever, this finding suggests that paracetamol inhibits fever by specifically blocking prostaglandin E2 synthesis in blood‐brain barrier endothelium. In another symptom of inflammation, anorexia, the cellular origin of peripheral signals triggering acute anorexia are largely unknown. We show that the expression of myeloid differentiation primary response gene 88 (Myd88) in myeloid cells is important for the initiation of acute inflammatory anorexia and the maintenance of cancer anorexia‐cachexia.

Taken together, these findings provide a significant advancement of our understanding of the mechanisms triggering acute inflammatory fever and anorexia and also explain the antipyretic effect of paracetamol.

sted, utgiver, år, opplag, sider
Linköping: Linköping University Electronic Press, 2014. s. 58
Serie
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1429
HSV kategori
Identifikatorer
urn:nbn:se:liu:diva-111727 (URN)978-91-7519-190-4 (ISBN)
Disputas
2014-12-05, Berzeliussalen, Campus US, Linköpings universitet, Linköping, 09:00 (engelsk)
Opponent
Veileder
Tilgjengelig fra: 2014-10-29 Laget: 2014-10-29 Sist oppdatert: 2017-07-07bibliografisk kontrollert

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