Impaired febrile response in mice lacking the prostaglandin E receptor subtype EP3.
Fever, a hallmark of disease, is elicited by exogenous pyrogens, that is, cellular components, such as lipopolysaccharide (LPS), of infectious organisms, as well as by non-infectious inflammatory insults. Both stimulate the production of cytokines, such as interleukin (IL)-1beta, that act on the brain as endogenous pyrogens. Fever can be suppressed by aspirin-like anti-inflammatory drugs. As these drugs share the ability to inhibit prostaglandin biosynthesis, it is thought that a prostaglandin is important in fever generation. Prostaglandin E2 (PGE2) may be a neural mediator of fever, but this has been much debated. PGE2 acts by interacting with four subtypes of PGE receptor, the EP1, EP2, EP3 and EP4 receptors. Here we generate mice lacking each of these receptors by homologous recombination. Only mice lacking the EP3 receptor fail to show a febrile response to PGE2 and to either IL-1beta or LPS. Our results establish that PGE2 mediates fever generation in response to both exogenous and endogenous pyrogens by acting at the EP3 receptor.
Ushikubi
F
F
Department of Pharmacology, Faculty of Medicine, Kyoto University, Japan.
Segi
E
E
Sugimoto
Y
Y
Murata
T
T
Matsuoka
T
T
Kobayashi
T
T
Hizaki
H
H
Tuboi
K
K
Katsuyama
M
M
Ichikawa
A
A
Tanaka
T
T
Yoshida
N
N
Narumiya
S
S
D000818:Animals; D003433:Crosses, Genetic; D015232:Dinoprostone / Q000494:pharmacology; D005334:Fever / Q000139:chemically induced / Q000209:etiology* / Q000378:metabolism; D018390:Gene Targeting; D007375:Interleukin-1 / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D011749:Pyrogens / Q000494:pharmacology; D018078:Receptors, Prostaglandin E / Q000235:genetics / Q000502:physiology*; D058308:Receptors, Prostaglandin E, EP3 Subtype
D007375:Interleukin-1; D008070:Lipopolysaccharides; C545648:Ptger3 protein, mouse; D011749:Pyrogens; D018078:Receptors, Prostaglandin E; D058308:Receptors, Prostaglandin E, EP3 Subtype; D015232:Dinoprostone