title: Cyclooxygenase Isoform Exchange Blocks Brain-Mediated Inflammatory Symptoms.
abstract: Cyclooxygenase-2 (COX-2) is the main source of inducible prostaglandin E2 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.
authors.affiliation: Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden.|Division of Drug Research/Emergency Medicine, Department of Medical and Health Sciences, Linköping University, Linköping, Sweden.|Department of Emergency Medicine, Linköping University Hospital, Linköping, Sweden.
authors.forename: Daniel
authors.identifier: http://orcid.org/0000-0001-6347-3970
authors.initials: D
authors.lastname: Björk Wilhelms
authors.affiliation: Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden.
authors.forename: Elahe
authors.initials: E
authors.lastname: Mirrasekhian
authors.affiliation: Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden.
authors.forename: Joanna
authors.initials: J
authors.lastname: Zajdel
authors.affiliation: Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden.
authors.forename: Anand
authors.initials: A
authors.lastname: Kumar Singh
authors.affiliation: Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden.
authors.forename: David
authors.initials: D
authors.lastname: Engblom
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism* / Q000473:pathology; D051545:Cyclooxygenase 1 / Q000235:genetics / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D015870:Gene Expression; D007249:Inflammation / Q000175:diagnosis* / Q000209:etiology / Q000378:metabolism*; D007527:Isoenzymes; D008070:Lipopolysaccharides / Q000009:adverse effects; D051379:Mice; D018345:Mice, Knockout; D010641:Phenotype; D011451:Prostaglandin-Endoperoxide Synthases / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism
chemical_list: D007527:Isoenzymes; D008070:Lipopolysaccharides; D012333:RNA, Messenger; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases