Role of the EP2 and EP4 receptor in the prostaglandin E2-mediated feedbackinhibition of lipopolysaccharide-induced TNF-alpha formation in mouse Kupffer cells

PGE(2) that is released in response to TNF-alpha inhibits the LPS-stimulate d TNF-alpha production in Kupffer cells in an autocrine feedback inhibition loop that is mediated by an increase in intracellular cAMP Kupffer cells p ossess two subtypes of Gs-coupled receptors for PGE(2) the EP2-R and the EP 4-R, that might be involved in this signal chain. By the use of EP2-R-defic ient mice it was analyzed which of the two receptor subtypes is involved in this signal chain. PGE(2) and an EP4-R specific agonist inhibited the LPS- induced TNF-alpha formation in Kupffer cells of control mice to a similar e xtent as in EP2-R deficient mice whereas an EP2-R specific agonist was effe ctive in control mice but failed to inhibit the LPS-stimulated TNF producti on in EP2-R-deficient mice. It is concluded that the EP2-R and the EP4-R ac t in parallel in KC to inhibit the LPS-induced TNF-alpha production.