The anti‐inflammatory effects of PGE 2 on human lung macrophages are mediated by the EP 4 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‐α and IL‐6 from macrophages were evaluated. The effects of EP 2 ‐selective (PF‐04852946, PF‐04418948) and EP 4 ‐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 lung macrophages. Analysis of mRNA levels indicated that macrophages expressed EP 2 and EP 4 receptors. L‐902,688 (EP 4 receptor‐selective agonist) was considerably more potent than butaprost (EP 2 receptor‐selective agonist) as an inhibitor of TNF‐α generation from macrophages. EP 2 receptor‐selective antagonists had marginal effects on the PGE 2 inhibition of TNF‐α generation, whereas EP 4 receptor‐selective antagonists caused rightward shifts in the PGE 2 concentration–response curves. Conclusions and Implications These studies demonstrate that the EP 4 receptor is the principal receptor that mediates the anti‐inflammatory effects of PGE 2 on human lung macrophages. This suggests that EP 4 receptor agonists could be effective anti‐inflammatory agents in human lung disease.