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Prostaglandin E2 in immune-to-brain signaling
Linköping University, Department of Biomedicine and Surgery, Cell biology. Linköping University, Faculty of Health Sciences.
2003 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Upon immune-challenge, signaling from the immune system to the brain triggers an array of central nervous responses that include fever, anorexia, hyperalgesia and activation of the hypothalamus-pituitary adrenal axis. These symptoms are dependent on cytokines produced at the site of inflammation. However, because cytokines cannot penetrate the blood-brain barrier, the mechanism by which cytokines activate the central nervous system has remained elusive. Among several hypotheses, it has been suggested that prostaglandin E2 (PGE2) synthesized at the blood-brain interface and subsequently binding to PGE2 receptors expressed on deep neural structures may be responsible for the immune-to-brain signaling.

During inflammatory conditions PGE2 is produced from prostaglandin H2 by the inducible isomerase microsomal prostaglandin E synthase-1 (mPGES-1). By using in situ hybridization, we investigated the expression of this enzyme in the brain of rats subjected to immune challenge induced by intravenous injection of interleukin-1ß. We found that mPGES-1 mRNA had a very restricted and low expression in the brain of naive rats. However, in response to inunune challenge it was rapidly and heavily induced in cells of the cerebral vasculature. Further, we found that the cells expressing mPGES-1 co-expressed cyclooxygenase-2 mRNA and interleukin-1 receptor type 1 mRNA. Thus, circulating interleukin-1 may bind to brain vascular cells and induce the expression of cyclooxygenase-2 and mPGES-1, leading to the production of PGE2 that can diffuse into the brain and trigger central nervous responses. We also showed that the same mechanism may be operating in a model for autoimmune disease. Thus, rats with adjuvant-induced arthritis, a model of rheumatoid arthritis, displayed a similar mPGES-1 and cyclooxygenase-2 induction in interleukin-1 receptor bearing brain endothelial cells.

To examine the functional role of the central induction of mPGES-1, we studied the febrile response in mice deficient in the gene encoding mPGES-1. These mice showed no fever and no central PGE2 production in response to immune challenge induced by intraperitoneal injection of the bacterial fragment lipopolysaccharide, demonstrating that PGE2 synthesized by mPGES-1 is critical for immune-induced fever.

We also studied the expression of receptors for PGE2 in the parabrachial nucleus, an autonomic brain stem structure involved in the regulation of food intake, blood pressure and nociceptive processing. We found that neurons in the para brachial nucleus express PGE2 receptors of type EP3 and EP4 and that many of the EP3 and some of the EP4 expressing neurons in this nucleus are activated by immune challenge. The PGE2 receptor expressing neurons also expressed mRNAs for various neuropeptides, such as dynorphin, enkephalin, calcitonin gene related peptide and substance P. Taken together with previous observations, these findings indicate that the PGE2 receptor expressing cells in the parabrachial nucleus are involved in alterations in food intake and in nociceptive processing during immune challenge.

In summary, these data show the presence of a mechanism, involving cerebrovascular induction of mPGES-1, that conveys an inflammatory message from the blood-stream through the blood-brain barrier to relevant deep neural structures. Further, the findings show that this mechanism is critical for the febrile response and is activated during both acute and prolonged inflammatory conditions. This identifies mPGES-1 as a potential drug target for the alleviation of central nervous symptoms of inflammatory disease, such as fever, pain and anorexia.

Place, publisher, year, edition, pages
Linköping: Linköpings universitet , 2003. , 100 p.
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 801
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:liu:diva-25641Local ID: 10016ISBN: 91-7373-492-6 (print)OAI: oai:DiVA.org:liu-25641DiVA: diva2:246189
Public defence
2003-09-19, Elsa Brändströmsalen, Hälsouniversitet, Linköping, 09:00 (Swedish)
Opponent
Available from: 2009-10-08 Created: 2009-10-08 Last updated: 2012-10-11Bibliographically approved
List of papers
1. Inflammatory response: pathway across the blood–brain barrier
Open this publication in new window or tab >>Inflammatory response: pathway across the blood–brain barrier
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2001 (English)In: Nature, ISSN 0028-0836, Vol. 410, 430-431 p.Article in journal (Refereed) Published
Abstract [en]

No abstract available.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-24947 (URN)10.1038/35068632 (DOI)000167583800030 ()9356 (Local ID)9356 (Archive number)9356 (OAI)
Available from: 2009-10-07 Created: 2009-10-07 Last updated: 2012-10-11Bibliographically approved
2. Induction of microsomal prostaglandin E synthase in the rat brain endothelium and parenchyma in adjuvant-induced arthritis
Open this publication in new window or tab >>Induction of microsomal prostaglandin E synthase in the rat brain endothelium and parenchyma in adjuvant-induced arthritis
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2002 (English)In: Journal of Comparative Neurology, ISSN 0021-9967, E-ISSN 1096-9861, Vol. 452, no 3, 205-214 p.Article in journal (Refereed) Published
Abstract [en]

Although central nervous symptoms such as hyperalgesia, fatigue, malaise, and anorexia constitute major problems in the treatment of patients suffering from chronic inflammatory disease, little has been known about the signaling mechanisms by which the brain is activated during such conditions. Here, in an animal model of rheumatoid arthritis, we show that microsomal prostaglandin E-synthase, the inducible terminal isomerase in the prostaglandin E2-synthesizing pathway, is expressed in endothelial cells along the blood-brain barrier and in the parenchyma of the paraventricular hypothalamic nucleus. The endothelial cells but not the paraventricular hypothalamic cells displayed a concomitant induction of cyclooxygenase-2 and expressed interleukin-1 type 1 receptors, which indicates that the induction is due to peripherally released cytokines. In contrast to cyclooxygenase-2, microsomal prostaglandin E synthase had very sparse constitutive expression, suggesting that it could be a target for developing drugs that will carry fewer side effects than the presently available cyclooxygenase inhibitors. These findings, thus, suggest that immune-to-brain communication during chronic inflammatory conditions involves prostaglandin E2-synthesis both along the blood-brain barrier and in the parenchyma of the hypothalamic paraventricular nucleus and point to novel avenues for the treatment of the brain-elicited disease symptoms during these conditions.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-24943 (URN)10.1002/cne.10380 (DOI)9352 (Local ID)9352 (Archive number)9352 (OAI)
Available from: 2009-10-07 Created: 2009-10-07 Last updated: 2012-10-11Bibliographically approved
3. Microsomal prostaglandin E synthase-1 is the central switch during immune-induced pyresis
Open this publication in new window or tab >>Microsomal prostaglandin E synthase-1 is the central switch during immune-induced pyresis
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2003 (English)In: Nature Neuroscience, ISSN 1097-6256, Vol. 6, no 11, 1137-1138 p.Article in journal (Refereed) Published
Abstract [en]

We studied the febrile response in mice deficient in microsomal prostaglandin E synthase-1 (mPGES-1), an inducible terminal isomerase expressed in cytokine-sensitive brain endothelial cells. These animals showed no fever and no central prostaglandin (PG) E2 synthesis after peripheral injection of bacterial-wall lipopolysaccharide, but their pyretic capacity in response to centrally administered PGE2 was intact. Our findings identify mPGES-1 as the central switch during immune-induced pyresis and as a target for the treatment of fever and other PGE2-dependent acute phase reactions elicited by the brain.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-24954 (URN)10.1038/nn1137 (DOI)9365 (Local ID)9365 (Archive number)9365 (OAI)
Available from: 2009-10-07 Created: 2009-10-07 Last updated: 2012-10-11Bibliographically approved
4. Distribution of prostaglandin EP3 and EP4 receptor mRNA in the rat parabrachial nucleus
Open this publication in new window or tab >>Distribution of prostaglandin EP3 and EP4 receptor mRNA in the rat parabrachial nucleus
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2000 (English)In: Neuroscience Letters, ISSN 0304-3940, E-ISSN 1872-7972, Vol. 281, no 2-3, 163-166 p.Article in journal (Refereed) Published
Abstract [en]

By using in situ hybridization, the distribution of mRNA for the PGE2 receptors EP3 and EP4 was examined in the rat parabrachial nucleus (PB), a major brain stem relay for autonomic and nociceptive processing. EP3 receptor mRNA was present in most subnuclei, with the densest labeling in the external lateral, dorsal lateral, superior lateral, central lateral and Kölliker–Fuse nuclei. EP4 receptor mRNA expressing cells had a more restricted distribution, largely being confined to the superior lateral and adjacent parts of the dorsal and central lateral nuclei in a pattern complementary to that for EP3 receptor mRNA. These findings suggest that EP3 and EP4 receptors in PB have distinct functional roles that include nociceptive processing, blood pressure regulation and feeding behavior.

Place, publisher, year, edition, pages
Elsevier Science B.V., Amsterdam., 2000
Keyword
inflammation; pain; in situ hybridization; Kolliker-Fuse nucleus
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-59666 (URN)10.1016/S0304-3940(00)00852-1 (DOI)000085886400023 ()10704768 (PubMedID)
Available from: 2010-09-23 Created: 2010-09-23 Last updated: 2017-12-12Bibliographically approved
5. Activation of prostanoid EP3 and EP4 receptor mRNA-expressing neurons in the rat parabrachial nucleus by intravenous injection of bacterial wall lipopolysaccharide
Open this publication in new window or tab >>Activation of prostanoid EP3 and EP4 receptor mRNA-expressing neurons in the rat parabrachial nucleus by intravenous injection of bacterial wall lipopolysaccharide
2001 (English)In: Journal of Comparative Neurology, ISSN 0021-9967, E-ISSN 1096-9861, Vol. 440, no 4, 378-386 p.Article in journal (Refereed) Published
Abstract [en]

Systemic inflammation activates central autonomic circuits, such as neurons in the pontine parabrachial nucleus. This activation may be the result of afferent signaling through the vagus nerve, but it may also depend on central prostaglandin-mediated mechanisms. Recently, we have shown that neurons in the parts of the parabrachial nucleus that are activated by immune challenge express prostaglandin receptors of the EP3 and EP4 subtypes, but it remains to be determined if the prostaglandin receptor-expressing neurons are identical to those that respond to immune stimuli. In the present study, bacterial wall lipopolysaccharide was injected intravenously in adult male rats and the expression of c-fos mRNA and of EP3 and EP4 receptor mRNA was examined with complementary RNA probes labeled with digoxigenin and radioisotopes, respectively. Large numbers of neurons in the external lateral parabrachial subnucleus, a major target of vagal-solitary tract efferents, expressed c-fos mRNA. Quantitative analysis showed that about 60% (range 40%–79%) of these neurons also expressed EP3 receptor mRNA. Conversely, slightly more than 50% (range 48%–63%) of the EP3 receptor-expressing neurons in the same subnucleus coexpressed c-fos mRNA. In contrast, few EP4 receptor-expressing neurons were c-fos positive, with the exception of a small population located in the superior lateral and dorsal lateral subnuclei. These findings show that immune challenge activates central autonomic neurons that could be the target of centrally produced prostaglandin E2, suggesting that synaptic signaling and paracrine mechanisms may interact on these neurons. J. Comp. Neurol. 440:378–386, 2001. © 2001 Wiley-Liss, Inc.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-24938 (URN)10.1002/cne.1391 (DOI)000172034800004 ()9346 (Local ID)9346 (Archive number)9346 (OAI)
Available from: 2009-10-07 Created: 2009-10-07 Last updated: 2012-10-11Bibliographically approved
6. EP3 and EP4 receptor mRNA expression in peptidergic cell groups of the rat parabrachial nucleus
Open this publication in new window or tab >>EP3 and EP4 receptor mRNA expression in peptidergic cell groups of the rat parabrachial nucleus
2004 (English)In: Neuroscience, ISSN 0306-4522, E-ISSN 1873-7544, Vol. 126, no 4, 989-999 p.Article in journal (Refereed) Published
Abstract [en]

This study examines the distribution of prostaglandin E2 receptors of subtype EP3 and EP4 among brain stem parabrachial neurons that were characterized with respect to their neuropeptide expression. By using a dual-labeling in situ hybridization method, we show that preprodynorphin mRNA expressing neurons in the dorsal and central lateral subnuclei express EP3 receptor mRNA. Such receptors are also expressed in preproenkephalin, calcitonin gene related peptide and preprotachykinin mRNA positive neurons in the external lateral subnucleus, whereas preprodynorphin mRNA expressing neurons in this subnucleus are EP receptor negative. In addition, EP3 receptor expression is seen among some enkephalinergic neurons in the Kölliker-Fuse nucleus. Neurons in the central part of the cholecystokininergic population in the regions of the superior lateral subnucleus express EP4 receptor mRNA, whereas those located more peripherally express EP3 receptors. Taken together with previous findings showing that discrete peptidergic cell groups mediate nociceptive and/or visceral afferent information to distinct brain stem and forebrain regions, the present results suggest that the processing of this information in the parabrachial nucleus is influenced by prostaglandin E2. Recent work has shown that prostaglandin E2 is released into the brain following peripheral immune challenge; hence, the parabrachial nucleus may be a region where humoral signaling of peripheral inflammatory events may interact with neuronal signaling elicited by the same peripheral processes.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-22395 (URN)10.1016/j.neuroscience.2004.03.042 (DOI)1605 (Local ID)1605 (Archive number)1605 (OAI)
Available from: 2009-10-07 Created: 2009-10-07 Last updated: 2012-10-11Bibliographically approved

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