title: Acetaminophen reduces lipopolysaccharide-induced fever by inhibiting cyclooxygenase-2.
abstract: 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.
authors.affiliation: Division of Cell Biology, Department of Clinical and Experimental Medicine, Faculty of Health Sciences, Linköping University, S-581 85 Linköping, Sweden.
authors.forename: Linda
authors.initials: L
authors.lastname: Engström Ruud
authors.forename: Daniel Björk
authors.initials: DB
authors.lastname: Wilhelms
authors.forename: Anna
authors.initials: A
authors.lastname: Eskilsson
authors.forename: Ana Maria
authors.initials: AM
authors.lastname: Vasilache
authors.forename: Louise
authors.initials: L
authors.lastname: Elander
authors.forename: David
authors.initials: D
authors.lastname: Engblom
authors.forename: Anders
authors.initials: A
authors.lastname: Blomqvist
mesh_terms: D000082:Acetaminophen / Q000008:administration & dosage / Q000627:therapeutic use*; D000818:Animals; D058633:Antipyretics / Q000008:administration & dosage / Q000627:therapeutic use*; D051546:Cyclooxygenase 2 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D052246:Cyclooxygenase 2 Inhibitors / Q000008:administration & dosage / Q000627:therapeutic use*; D015232:Dinoprostone / Q000008:administration & dosage / Q000009:adverse effects; D004305:Dose-Response Relationship, Drug; D005334:Fever / Q000139:chemically induced / Q000188:drug therapy* / Q000201:enzymology / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D006579:Heterozygote; D007031:Hypothalamus / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D007276:Injections, Intraventricular; D019746:Intramolecular Oxidoreductases / Q000235:genetics / Q000378:metabolism; D008070:Lipopolysaccharides; D051379:Mice; D008811:Mice, Inbred DBA; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D016548:Prosencephalon / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D000071876:Prostaglandin-E Synthases
chemical_list: D058633:Antipyretics; D052246:Cyclooxygenase 2 Inhibitors; D008070:Lipopolysaccharides; D009419:Nerve Tissue Proteins; D000082:Acetaminophen; C077623:Ptgs2 protein, mouse; D051546:Cyclooxygenase 2; D019746:Intramolecular Oxidoreductases; D000071876:Prostaglandin-E Synthases; C000605865:Ptges protein, mouse; D015232:Dinoprostone