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Distribution of microsomal prostaglandin E synthase-1 in the mouse brain
Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Hälsouniversitetet.
Division of Membrane Transport and Drug Targeting, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Japan, Department of Pharmaceutics, Graduate School of Medicine and Pharmaceutical Sciences, University of of Toyama, Toyama, Japan; Department of Pharmaceutics, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama, Japan .
Department of Pharmaceutics, Graduate School of Medicine and Pharmaceutical Sciences, University of of Toyama, Toyama, Japan.
Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Hälsouniversitetet.
2014 (Engelska)Ingår i: Journal of Comparative Neurology, ISSN 0021-9967, E-ISSN 1096-9861, Vol. 522, nr 14, s. 3229-3244Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

Previous studies in rats have demonstrated that microsomal prostaglandin E synthase-1 (mPGES-1) is induced in brain vascular cells that also express inducible cyclooxygenase-2, suggesting that such cells are the source of the increased PGE2 levels that are seen in the brain following peripheral immune stimulation, and that are associated with sickness responses such as fever, anorexia, and stress hormone release. However, while most of what is known about the functional role of mPGES-1 for these centrally evoked symptoms is based on studies on genetically modified mice, the cellular localization of mPGES-1 in the mouse brain has not been thoroughly determined. Here, using a newly developed antibody that specifically recognizes mouse mPGES-1 and dual-labeling for cell-specific markers, we report that mPGES-1 is constitutively expressed in the mouse brain, being present not only in brain endothelial cells, but also in several other cell types and structures, such as capillary-associated pericytes, astroglial cells, leptomeninges, and the choroid plexus. Regional differences were seen with particularly prominent labeling in autonomic relay structures such as the area postrema, the subfornical organ, the paraventricular hypothalamic nucleus, the arcuate nucleus, and the preoptic area. Following immune stimulation, mPGES-1 in brain endothelial cells, but not in other mPGES-1-positive cells, was coexpressed with cyclooxygenase-2, whereas there was no coexpression between mPGES-1 and cyclooxygenase-1. These data imply a widespread synthesis of PGE2 or other mPGES-1-dependent products in the mouse brain that may be related to inflammation-induced sickness symptom as well as other functions, such as blood flow regulation.

Ort, förlag, år, upplaga, sidor
John Wiley & Sons, 2014. Vol. 522, nr 14, s. 3229-3244
Nyckelord [en]
Astroglial cells; Cyclooxygenase; Endothelial cells; Immune challenge; Pericytes; Prostaglandin synthesis
Nationell ämneskategori
Klinisk medicin
Identifikatorer
URN: urn:nbn:se:liu:diva-109962DOI: 10.1002/cne.23593ISI: 000339967300006PubMedID: 24668417Scopus ID: 2-s2.0-84904553311OAI: oai:DiVA.org:liu-109962DiVA, id: diva2:746352
Tillgänglig från: 2014-09-12 Skapad: 2014-08-29 Senast uppdaterad: 2020-01-08
Ingår i avhandling
1. Inflammatory Signaling Across the Blood-Brain Barrier and the Generation of Fever
Öppna denna publikation i ny flik eller fönster >>Inflammatory Signaling Across the Blood-Brain Barrier and the Generation of Fever
2020 (Engelska)Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
Abstract [en]

Fever is a cardinal sign of inflammation and is evolutionary conserved. Fever is known to be beneficial during acute inflammation, but over time and if very high it can be detrimental. The signaling pathways by which fever is initiated by the brain and the peripheral mechanisms through which the temperature increase is generated were studied from several point of views. Fever is known to be dependent on prostaglandin E2 (PGE2) binding to its receptors in the median preoptic nucleus of the hypothalamus, which signals to the brainstem and through sympathetic nerves to heat conserving and heat producing effector organs. This thesis focuses on identifying the cells that produce the PGE2 critical for the fever response; showing where in the brain the critical PGE2 production takes place; demonstrating how peripheral inflammation activates these cells to produce PGE2; and finally, identifying the effector mechanisms behind the temperature elevation in fever. By using a newly developed specific antibody we showed that the enzyme responsible for the terminal step in the production of PGE2, microsomal prostaglandin E-synthase 1 (mPGES-1), is expressed in endothelial cells of brain blood vessels in mice where it is co-expressed with the enzyme cyclooxygenase-2 (Cox-2), which is known to be induced in these cells and to be rate limiting for the PGE2 production. The mPGES-1 enzyme was also expressed in several other cell types and structures which however did not express Cox-2, such as capillary-associated pericytes, astroglial cells, leptomeninges, and the choroid plexus. The role of the mPGES-1 in these other cells/structures remains unknown. Next, by using mice with selective deletion of Cox-2 in brain endothelial cells, we showed that local PGE2 production in deep brain areas, such as the hypothalamus, is critical for the febrile response to peripheral inflammation. In contrast, PGE2 production in other brain areas and the overall PGE2 level in the brain were not critical for the febrile response. Partly restoring the PGE2 synthesizing capacity in the anterior hypothalamus of mice lacking such capacity with a lentiviral vector resulted in a temperature elevation in response to an intraperitoneal injection of bacterial wall lipopolysaccharide (LPS). The data show that the febrile response is dependent on the local release of PGE2 onto its target neurons, possibly by a paracrine mechanism. Deletion of the receptor for the pyrogenic cytokine IL-6 on brain endothelial cells, but not on neurons or peripheral nerves, strongly attenuated the febrile response to LPS and reduced the induction of the Cox-2 expression in the hypothalamus. Furthermore, mice deficient of the IL- 6Rα gene in the brain endothelial cells showed a reduced SOCS3 mRNA induction, whereas IκB mRNA-levels were unaffected, suggesting that the IL-6 signaling occurs via STAT3 activation and not signaling through the transcription factor NF-κB. This idea was confirmed by the observation of attenuated fever in mice deficient of STAT3 in brain endothelial cells. These data show that IL-6, when endogenously released during systemic inflammation, is pyrogenic by binding to IL-6R on brain endothelial cells to induce prostaglandin synthesis in these cells. Finally, we demonstrate that mice with genetic deletion of uncoupling protein-1 (UCP-1), hence lacking functional brown adipose tissue, had a normal fever response to LPS, and that LPS caused no activation of brown adipose tissue in wild type mice. However, blocking peripheral cutaneous vasoconstriction resulted in a blunted fever response to LPS, suggesting that heat conservation, possibly together with shivering or non-shivering thermogenesis in the musculature, is responsible for the generation of immune-induced fever, whereas brown adipose tissue thermogenesis is not involved.  

Ort, förlag, år, upplaga, sidor
Linköping: Linköping University Electronic Press, 2020. s. 44
Serie
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1724
Nationell ämneskategori
Cell- och molekylärbiologi
Identifikatorer
urn:nbn:se:liu:diva-163003 (URN)10.3384/diss.diva-163003 (DOI)9789179299361 (ISBN)
Disputation
2020-02-14, Hasselqvistsalen, Building 511 Campus US, Linköping, 13:00 (Svenska)
Opponent
Handledare
Tillgänglig från: 2020-01-08 Skapad: 2020-01-08 Senast uppdaterad: 2020-01-24Bibliografiskt granskad

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