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 infectio us organisms, as well as by non-infectious inflammatory insults. Both stimulate the production of cytokines, such as interleukin (IL)-1 beta , that act on the brain as endogenous pyrogens'. Fever can be suppress ed by aspirin-like anti-inflammatory drugs. As these drugs share the a bility 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 deba ted(1,4-7). PGE, acts by interacting with four subtypes of PGE recepto r, the EP1, EP2, EP3 and EP4 receptors(8). Here we generate mice lacki ng each of these receptors by homologous recombination. Only mice lack ing the EP3 receptor fail to show a febrile response to PGE(2) and to either IL-1 beta or LPS. Our results establish that PGE(2) mediates fe ver generation in response to both exogenous and endogenous pyrogens b y acting at the EP3 receptor.