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)-1β, that act on the brain as endogenous pyrogens 1 . Fever can be suppressed by aspirin-like anti-inflammatory drugs. As these drugs share the ability to inhibit prostaglandin biosynthesis 2 , it is thought that a prostaglandin is important in fever generation. Prostaglandin E 2 (PGE 2 ) may be a neural mediator of fever 3 , but this has been much debated 1 , 4 , 5 , 6 , 7 . PGE 2 acts by interacting with four subtypes of PGE receptor, the EP 1 , EP 2 , EP 3 and EP 4 receptors 8 . Here we generate mice lacking each of these receptors by homologous recombination. Only mice lacking the EP 3 receptor fail to show a febrile response to PGE 2 and to either IL-1β or LPS. Our results establish that PGE 2 mediates fever generation in response to both exogenous and endogenous pyrogens by acting at the EP 3 receptor.