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Cyclooxygenase Isoform Exchange Blocks Brain-Mediated Inflammatory Symptoms
Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences. Linköping University, Department of Clinical and Experimental Medicine. Region Östergötland, Local Health Care Services in Central Östergötland, Department of Emergency Medicine.
Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.ORCID iD: 0000-0003-2245-3396
Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
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2016 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 11, no 11, article id e0166153Article in journal (Refereed) Published
Abstract [en]

Cyclooxygenase-2 (COX-2) is the main source of inducible prostaglandin E-2 production and mediates inflammatory symptoms including fever, loss of appetite and hyperalgesia. COX-1 is dispensable for fever, anorexia and hyperalgesia but is important for several other functions both under basal conditions and during inflammation. The differential functionality of the COX isoforms could be due to differences in the regulatory regions of the genes, leading to different expression patterns, or to differences in the coding sequence, resulting in distinct functional properties of the proteins. To study the molecular underpinnings of the functional differences between the two isoforms 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 as well as an impaired response to inflammatory pain. However, as previously reported, they displayed close to normal survival rates, which contrasts to the high fetal mortality in COX-2 knockout mice. This shows that the COX activity generated from the hybrid gene was strong enough to allow survival but not strong enough to mediate the inflammatory symptoms studied, 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 are 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.

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PUBLIC LIBRARY SCIENCE , 2016. Vol. 11, no 11, article id e0166153
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Developmental Biology
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URN: urn:nbn:se:liu:diva-133262DOI: 10.1371/journal.pone.0166153ISI: 000388350300029PubMedID: 27861574OAI: oai:DiVA.org:liu-133262DiVA, id: diva2:1057485
Note

Funding Agencies|European Research Council [260820]; Swedish Medical Research Council [25084, 25052, 77044]; Knut och Alice Wallenbergs Stiftelse; Hjarnfonden; County Council of Ostergotland

Available from: 2016-12-18 Created: 2016-12-15 Last updated: 2017-11-29Bibliographically approved

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