The anti-inflammatory effects of PGE2 on human lung macrophages are mediated by the EP4 receptor

BACKGROUND AND PURPOSE PGE(2) inhibits cytokine generation from human lung macrophages. However, the EP receptor that mediates this beneficial anti-inflammatory effect of PGE(2) has not been defined. The aim of this study was to identify the EP receptor by which PGE(2) inhibits cytokine generation from human lung macrophages. This was determined by using recently developed EP receptor ligands. EXPERIMENTAL APPROACH The effects of PGE(2) and EP-selective agonists on LPS-induced generation of TNF-alpha and IL-6 from macrophages were evaluated. The effects of EP2-selective (PF-04852946, PF-04418948) and EP4-selective (L-161,982, CJ-042794) receptor antagonists on PGE(2) responses were studied. The expression of EP receptor subtypes by human lung macrophages was determined by RT-PCR. KEY RESULTS PGE(2) inhibited LPS-induced and Streptococcus pneumoniae-induced cytokine generation from human lungmacrophages. Analysis of mRNA levels indicated that macrophages expressed EP2 and EP4 receptors. L-902,688 (EP4 receptor-selective agonist) was considerably more potent than butaprost (EP2 receptor-selective agonist) as an inhibitor of TNF-alpha generation from macrophages. EP2 receptor-selective antagonists had marginal effects on the PGE(2) inhibition of TNF-alpha generation, whereas EP4 receptorselective antagonists caused rightward shifts in the PGE(2) concentration-response curves. CONCLUSIONS AND IMPLICATIONS These studies demonstrate that the EP4 receptor is the principal receptor that mediates the anti-inflammatory effects of PGE(2) on human lung macrophages. This suggests that EP4 receptor agonists could be effective anti-inflammatory agents in human lung disease.