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Expression of PGE2 EP3 receptor subtypes in the mouse preoptic region
Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Division of cell biology.
Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Division of cell biology.ORCID iD: 0000-0002-2230-4174
2007 (English)In: Neuroscience Letters, ISSN 0304-3940, Vol. 423, no 3, 179-183 p.Article in journal (Refereed) Published
Abstract [en]

Inflammatory-induced fever is dependent on prostaglandin E2 (PGE2) binding to its EP3 receptor in the thermoregulatory region of the hypothalamus, but it is not known which EP3 receptor isoform(s) that is/are involved. We identified the EP3 receptor expression in the mouse preoptic region by in situ hybridization and isolated the corresponding area by laser capture microdissection. Real-time RT-PCR analysis of microdissected tissue revealed a predominant expression of the EP3α isoform, but there was also considerable expression of EP3γ, corresponding to approximately 15% of total EP3 receptor expression, whereas EP3β was sparsely expressed. This distribution was not changed by immune challenge induced by peripheral administration of LPS, indicating that EP3 receptor splicing and distribution is not activity dependent. Considering that EP3α and EP3γ are associated with inhibitory and stimulatory G-proteins, respectively, the present data demonstrate that the PGE2 response of the target neurons is intricately regulated. © 2007 Elsevier Ireland Ltd. All rights reserved.

Place, publisher, year, edition, pages
2007. Vol. 423, no 3, 179-183 p.
National Category
Medical and Health Sciences
URN: urn:nbn:se:liu:diva-39503DOI: 10.1016/j.neulet.2007.06.048Local ID: 49060OAI: diva2:260352
Available from: 2009-10-10 Created: 2009-10-10 Last updated: 2016-05-04
In thesis
1. Talking to the Brain at the Blood-Brain Barrier through Inflammation-Induced Prostaglandin E2
Open this publication in new window or tab >>Talking to the Brain at the Blood-Brain Barrier through Inflammation-Induced Prostaglandin E2
2015 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The immune-to-brain signaling is a critical survival factor when the body is confronted by pathogens, and in particular by microorganisms. During infections, the ability of the immune system to engage the central nervous system (CNS) in the management of the inflammatory response is just as important as its ability to mount a specific immune response against the pathogen, since the CNS can provide a systemic negative feed-back to the immune activation by release of stress hormones and also can prioritize the usage of the energy resources by the vital organs. Prostaglandin E2 (PGE2) and proinflammatory cytokines were among the first mediators to be identified to participate in the immuneto-brain signaling, a process that is clinically recognized by the development of manifestations of common illness such as fever, anorexia, decreased social interactions, lethargy, sleepiness, and hyperalgesia.

In this thesis the contribution of PGE2 to the immune-to-brain signaling was further characterized at the blood-brain-barrier (BBB) and in the anterior preoptic area (POA) of the hypothalamus (i.e. the thermoregulatory region or, in sickness, the fever generating region).

BBB is the major interface region between peripheral circulating cytokines and the neuronal parenchyma and a critical source of PGE2. Using chimeric mice lacking the inducible enzyme for PGE2 synthesis, microsomal PGE synthase-1 (mPGES-1), in either hematopoietic or non-hematopoietic cells, we demonstrate in paper I that brain endothelial cells are the critical source of PGE2 in BBB during peripheral inflammation. For the demonstration of the mPGES-1 expression in the BBB cells we developed in paper I a method for enzymatic dissociation of these cells, followed by fluorescence activated cell sorting (FACS). Using the same method, we show in paper II that the BBB response to immune stimuli is towards an increased production of PGE2 in endothelial cells and an increased sensitivity of these cells for pro-inflammatory cytokines. These changes are supported by decreased PGE2 degradation and decreased synthesis of other prostanoids in perivascular macrophages, which hence respond in concordance with the endothelial cells in enhancing PGE2 signaling.

Once released in the neuronal tissue, PGE2 has been shown to be critical for the fever response by acting on the type 3 PGE2 receptors (EP3) within POA. By laser capture microdissection (LCM) we extracted the EP3 receptor expressing region in POA, defined by in situ hybridization histochemistry, from mouse brain sections. We demonstrate in paper III that the predominant subtypes of the EP3 receptor in POA are EP3α and EP3γ. In paper IV we further analyze the effect of PGE2 on the LCM dissected EP-rich POA using gene expression microarrays. We demonstrate that PGE2 has a limited effect on the gene expression changes within POA, suggesting that the neuronal activity is modulated by PGE2 in a transcription-independent manner and that the profound gene expression changes that are seen in the CNS during inflammation are accordingly PGE2-independent.

Place, publisher, year, edition, pages
Linköping: Linköping University Electronic Press, 2015. 99 p.
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1435
National Category
Cell and Molecular Biology Cell Biology
urn:nbn:se:liu:diva-114378 (URN)10.3384/diss.diva-114378 (DOI)978-91-7519-155-3 (print) (ISBN)
Public defence
2015-03-20, Berzeliussalen, Campus US, Linköpings universitet, Linköping, 13:15 (Swedish)
Available from: 2015-02-19 Created: 2015-02-19 Last updated: 2016-05-04Bibliographically approved

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Vasilache, Ana-MariaNilsberth, Camilla
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