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Cyclooxygenase isoform exchange blocks inflammatory symptoms
Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences.
Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences.ORCID iD: 0000-0003-2245-3396
Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences.
2014 (English)Manuscript (preprint) (Other academic)
Abstract [en]

Cyclooxygenase‐2 (COX‐2) is the main source of inducible prostaglandin E2 production and mediates inflammatory symptoms including fever, loss of appetite and hyperalgesia. In contrast, COX‐1 is dispensable for most inflammatory symptoms. Global deletion of COX‐2 leads to a blockade of inflammation‐induced fever and appetite loss but also to high rates of fetal mortality. The latter is unfortunate since mice without COX‐2 are powerful tools in the study of inflammation and cardiovascular medicine. The differential functionality of the COX isoforms could be due to differences in regulatory regions of the genes, leading to different expression patterns, or to differences in the coding sequence, leading to distinct functional properties of the proteins. To study this in the context of inflammatory symptoms, we used mice in which the coding sequence of COX‐2 was replaced by the corresponding sequence of COX‐1. In these mice, COX‐1 mRNA was induced by inflammation but COX‐1 protein expression did not fully mimic inflammation‐induced COX‐2 expression. Just like mice globally lacking COX‐2, these mice showed a complete lack of fever and inflammation‐induced anorexia. However, as previously reported, they displayed close to normal survival rates. This shows that the COX activity generated from the hybrid gene was strong enough to allow survival but not strong enough to mediate inflammatory symptoms, making the line an interesting alternative to COX‐2 knockouts for the study of inflammation. Our results also show that the functional differences between COX‐1 and COX‐2 in the context of inflammatory symptoms is not only dependent on the features of the promoter regions. Instead they indicate that there are fundamental differences between the isoforms at translational or posttranslational levels, which make hybrid genes less functional.

Place, publisher, year, edition, pages
2014.
National Category
Cell Biology Rheumatology and Autoimmunity
Identifiers
URN: urn:nbn:se:liu:diva-111725OAI: oai:DiVA.org:liu-111725DiVA: diva2:759129
Available from: 2014-10-29 Created: 2014-10-29 Last updated: 2015-11-06Bibliographically approved
In thesis
1. Fever: Role of brain endothelial prostaglandins
Open this publication in new window or tab >>Fever: Role of brain endothelial prostaglandins
2014 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Fever and loss of appetite are two of the most fundamental manifestations of disease. These disease symptoms, which lead to deviations from normal body temperature and food intake patterns, are seen in a vast array of infectious and inflammatory conditions. It is known that peripheral signals from the immune system are essential triggers for these responses, which are orchestrated by neuronal circuits in the brain. Due to the blood‐brain barrier, peripheral inflammatory signals require a specific mode of transmission into the brain. Such mechanisms have been proposed, but interventional studies of these mechanisms have never rendered conclusive results. In this thesis, we present the first functional evidence of cyclooxygenase 2 (COX‐2) and microsomal prostaglandin E synthase type 1 (mPGES‐1) mediated prostaglandin E2 synthesis in the blood‐brain barrier endothelial cells as a signaling mechanism in the initiation of inflammatory fever. We also show that one of the world’s most widely used antipyretics, paracetamol, acts by inhibition of COX‐2. Combined with the finding that COX‐2 and mPGES‐1 in brain endothelial cells play a key role in inflammatory fever, this finding suggests that paracetamol inhibits fever by specifically blocking prostaglandin E2 synthesis in blood‐brain barrier endothelium. In another symptom of inflammation, anorexia, the cellular origin of peripheral signals triggering acute anorexia are largely unknown. We show that the expression of myeloid differentiation primary response gene 88 (Myd88) in myeloid cells is important for the initiation of acute inflammatory anorexia and the maintenance of cancer anorexia‐cachexia.

Taken together, these findings provide a significant advancement of our understanding of the mechanisms triggering acute inflammatory fever and anorexia and also explain the antipyretic effect of paracetamol.

Place, publisher, year, edition, pages
Linköping: Linköping University Electronic Press, 2014. 58 p.
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1429
National Category
Cell Biology
Identifiers
urn:nbn:se:liu:diva-111727 (URN)978-91-7519-190-4 (ISBN)
Public defence
2014-12-05, Berzeliussalen, Campus US, Linköpings universitet, Linköping, 09:00 (English)
Opponent
Supervisors
Available from: 2014-10-29 Created: 2014-10-29 Last updated: 2017-07-07Bibliographically approved

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Björk Wilhelms, DanielMirrasekhian, ElaheEngblom, David

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