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Minor Changes in Gene Expression in the Mouse Preoptic Hypothalamic Region by Inflammation-Induced Prostaglandin E2
Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Diagnostikcentrum, Klinisk immunologi och transfusionsmedicin.
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.
Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Hälsouniversitetet.ORCID-id: 0000-0002-2230-4174
2013 (engelsk)Inngår i: Journal of neuroendocrinology (Print), ISSN 0953-8194, E-ISSN 1365-2826, Vol. 25, nr 7, s. 635-643Artikkel i tidsskrift (Fagfellevurdert) Published
Abstract [en]

We investigated to what extent inflammation-induced prostaglandin E2 (PGE2) regulates gene expression in the central nervous system. Wild-type mice and mice with deletion of the gene encoding microsomal prostaglandin E synthase-1 (mPGES-1), which cannot produce inflammation-induced PGE2, were subjected to peripheral injection of bacterial wall lipopolysaccharide (LPS) and killed after 5 h. The median and medial preoptic nuclei, which are rich in prostaglandin E receptors, were isolated by laser capture microdissection (LCM), and subjected to whole genome microarray analysis. Although the immune stimulus induced robust transcriptional changes in the brain, as seen by a quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR) on selected genes, only small PGE2-dependent gene expression changes were observed in the gene array analysis and, for only two genes, a pronounced differential expression between LPS-treated wild-type and mPGES-1 knockout mice could be verified by qRT-PCR. These were Hspa1a and Hspa1b, encoding heat shock proteins, which showed a two- to three-fold higher expression in wild-type mice than in knockout mice after immune challenge. However, the induced expression of these genes was found to be secondary to increased body temperature because they were induced also by cage exchange stress, which did not elicit PGE2 synthesis, and thus were not induced per se by PGE2-elicited transcriptional events. Our findings suggest that inflammation-induced PGE2 has little effect on gene expression in the preoptic region, and that centrally elicited disease symptoms, although PGE2-dependent, occur as a result of regulation of neuronal excitability that is a consequence of intracellular, transcriptional-independent signalling cascades. Our findings also imply that the profound changes in gene expression in the brain that are elicited by peripheral inflammation occur independently of PGE2 via a yet unidentified mechanism.

sted, utgiver, år, opplag, sider
Wiley-Blackwell , 2013. Vol. 25, nr 7, s. 635-643
Emneord [en]
microsomal prostaglandin E synthase-1; prostaglandin E2; fever; preoptic region; laser capture microdissection; whole genome microarray; heat-shock proteins
HSV kategori
Identifikatorer
URN: urn:nbn:se:liu:diva-96460DOI: 10.1111/jne.12044ISI: 000320402900005OAI: oai:DiVA.org:liu-96460DiVA, id: diva2:642932
Tilgjengelig fra: 2013-08-23 Laget: 2013-08-20 Sist oppdatert: 2017-12-06bibliografisk kontrollert
Inngår i avhandling
1. Talking to the Brain at the Blood-Brain Barrier through Inflammation-Induced Prostaglandin E2
Åpne denne publikasjonen i ny fane eller vindu >>Talking to the Brain at the Blood-Brain Barrier through Inflammation-Induced Prostaglandin E2
2015 (engelsk)Doktoravhandling, med artikler (Annet vitenskapelig)
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.

sted, utgiver, år, opplag, sider
Linköping: Linköping University Electronic Press, 2015. s. 99
Serie
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1435
HSV kategori
Identifikatorer
urn:nbn:se:liu:diva-114378 (URN)10.3384/diss.diva-114378 (DOI)978-91-7519-155-3 (ISBN)
Disputas
2015-03-20, Berzeliussalen, Campus US, Linköpings universitet, Linköping, 13:15 (svensk)
Opponent
Veileder
Tilgjengelig fra: 2015-02-19 Laget: 2015-02-19 Sist oppdatert: 2019-11-15bibliografisk kontrollert

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