Contribution of the two gs-coupled PGE2-receptors EP2-receptor and EP4-receptor to the inhibition by PGE2 of the LPS-induced TNFα-information in Kupffer cells from EP2-or EP4-receptor-deficient mice.: Pivotal role for the EP4-receptor in wild type Kupffer cells

Background/Aims: Prostaglandin E-2 (PGE(2)) is known to inhibit the lipopolysaccharide (LPS)-induced tumor necrosis factor alpha (TNFalpha) formation in Kupffer cells via an increase in cAMP. Four receptor-subtypes have been cloned for PGE(2) so far. Two of them, the EP2-receptor and the EP4-receptor are linked to stimulatory Gs-proteins and could mediate the inhibition by PGE(2) of TNFalpha-formation. Methods: The significance of both receptors for PGE(2)-dependent inhibition of LPS-induced TNFalpha-formation was studied using Kupffer cells of mice in which either one of the two receptors had been eliminated by homologous recombination. Results: The mRNAs of both receptors were expressed in wild type mouse Kupffer cells. Exogenous PGE(2) inhibited TNFalpha-formation in Kupffer cells lacking either EP2-receptor or EP4-receptor to a similar extent as in control cells, however, 10-fold higher PGE(2) concentrations were needed for half maximal inhibition in cells lacking the EP4-receptor than in control or EP2-receptor-deficient cells. The response to endogenous PGE(2) was blunted in EP4-receptor-deficient mice only and especially after prolonged incubation. Conclusions: The data indicate, that PGE(2) can inhibit TNFalpha-formation via both the EP2- and the EP4-receptor and that, however, the EP4-receptor appears to be physiologically more relevant in Kupffer cells since it conferred a high affinity response to PGE(2). (C) 2002 European Association for the Study of the Liver. Published by Elsevier Science B.V. All rights reserved.