EP3 is the only prostaglandin E receptor required for lipopolysaccharide-induced fever.

Fever induced by systemic inflammation is mediated by prostaglandin E2 (PGE2), but the identity of the prostaglandin E (EP) receptor subtype responsible for the febrile response remains debated. Although EP3 receptors have been strongly implicated in fever generation, studies using pharmacological approaches and receptor-deficient mice have also suggested involvement of EP1 and EP4 receptors. Because previous studies have differed substantially with regard to experimental conditions, including ambient temperature, route of immune challenge, and injection-associated stress responses, we systematically compared the febrile response to lipopolysaccharide (LPS) in mice lacking EP1, EP2, EP3, or EP4 receptors under standardized physiological conditions. Body temperature was recorded by telemetry in mice housed at thermoneutrality and injected intravenously with LPS (30 μg/kg) through indwelling jugular catheters, permitting remote injections with minimal disturbance to the animals. Mice with global deletion of EP1, EP2, or EP3, as well as mice with nervous system-directed deletion of EP4, all maintained on a C57BL/6 background, were examined together with wild-type littermates. Wild-type mice displayed a characteristic multiphasic fever following LPS administration. Mice lacking EP1 or EP2, or with nervous system-directed deletion of EP4, exhibited febrile responses indistinguishable from those of their wild-type controls. In contrast, mice lacking EP3 failed completely to develop fever and instead displayed a pronounced hypothermic response immediately following LPS injection. These findings identify EP3 as the only prostaglandin E receptor with a non-redundant role in LPS-induced fever and support the concept that EP3-dependent signaling constitutes the final common pathway for inflammatory fever.