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Induction of microsomal prostaglandin E synthase in the rat brain endothelium and parenchyma in adjuvant-induced arthritis
Linköping University, Department of Biomedicine and Surgery, Cell biology. Linköping University, Faculty of Health Sciences.
Department of Medicine, Unit of Rheumatology, The Karolinska Institute, Stockholm, Sweden.
Department of Medicine, Unit of Rheumatology, The Karolinska Institute, Stockholm, Sweden.
Center for Structural Biochemistry, The Karolinska Institute, Huddinge, Sweden.
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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.

Place, publisher, year, edition, pages
2002. Vol. 452, no 3, 205-214 p.
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:liu:diva-24943DOI: 10.1002/cne.10380Local ID: 9352OAI: oai:DiVA.org:liu-24943DiVA: diva2:245267
Available from: 2009-10-07 Created: 2009-10-07 Last updated: 2017-12-13Bibliographically approved
In thesis
1. Prostaglandin E2 in immune-to-brain signaling
Open this publication in new window or tab >>Prostaglandin E2 in immune-to-brain signaling
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:nbn:se:liu:diva-25641 (URN)10016 (Local ID)91-7373-492-6 (ISBN)10016 (Archive number)10016 (OAI)
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

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Engblom, DavidBlomqvist, Anders

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