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Acetaminophen reduces lipopolysaccharide-induced fever by inhibiting cyclooxygenase-2
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.
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. Östergötlands Läns Landsting, Center for Diagnostics, Department of Clinical Immunology and Transfusion Medicine.
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2013 (English)In: Neuropharmacology, ISSN 0028-3908, E-ISSN 1873-7064, Vol. 71, 124-129 p.Article in journal (Refereed) Published
Abstract [en]

Acetaminophen is one of the world's most commonly used drugs to treat fever and pain, yet its mechanism of action has remained unclear. Here we tested the hypothesis that acetaminophen blocks fever through inhibition of cyclooxygenase-2 (Cox-2), by monitoring lipopolysaccharide induced fever in mice with genetic manipulations of enzymes in the prostaglandin cascade. We exploited the fact that lowered levels of a specific enzyme make the system more sensitive to any further inhibition of the same enzyme. Mice were immune challenged by an intraperitoneal injection of bacterial wall lipopolysaccharide and their body temperature recorded by telemetry. We found that mice heterozygous for Cox-2, but not for microsomal prostaglandin E synthase-1 (mPGES-1), displayed attenuated fever, indicating a rate limiting role of Cox-2. We then titrated a dose of acetaminophen that did not inhibit the lipopolysaccharide-induced fever in wild-type mice. However, when the same dose of acetaminophen was given to Cox-2 heterozygous mice, the febrile response to lipopolysaccharide was strongly attenuated, resulting in an almost normalized temperature curve, whereas no difference was seen between wild-type and heterozygous mPGES-1 mice. Furthermore, the fever to intracerebrally injected prostaglandin E2 was unaffected by acetaminophen treatment. These findings reveal that acetaminophen, similar to aspirin and other non-steroidal anti-inflammatory drugs, is antipyretic by inhibiting cyclooxygenase-2, and not by inhibiting mPGES-1 or signaling cascades downstream of prostaglandin E2.

Place, publisher, year, edition, pages
Elsevier , 2013. Vol. 71, 124-129 p.
Keyword [en]
Fever; Cyclooxygenase-2; Cyclooxygenase-1; Microsomal prostaglandin E synthase-1; Gene dosage; Hypothalamus
National Category
Medical and Health Sciences
URN: urn:nbn:se:liu:diva-96170DOI: 10.1016/j.neuropharm.2013.03.012ISI: 000320424200012OAI: diva2:640812
Available from: 2013-08-14 Created: 2013-08-14 Last updated: 2014-10-29
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.
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1429
National Category
Cell Biology
urn:nbn:se:liu:diva-111727 (URN)978‐91‐7519‐190‐4 (print) (ISBN)
Public defence
2014-12-05, Berzeliussalen, Campus US, Linköpings universitet, Linköping, 09:00 (English)
Available from: 2014-10-29 Created: 2014-10-29 Last updated: 2014-10-29Bibliographically approved

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Engström, LindaBjörk, DanielEskilsson, AnnaVasilache, Ana-MariaElander, LouiseEngblom, DavidBlomqvist, Anders
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Division of Cell BiologyFaculty of Health SciencesDepartment of Clinical Immunology and Transfusion MedicineCell Biology
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