The anti-inflammatory effects of prostaglandin E 2 on human lung macrophages are mediated by the EP 4 receptor

Background and purpose: Prostaglandin E2 (PGE2) has been shown to inhibit cytokine generation from human lung macrophages. However, the EP receptor that mediates this beneficial anti-inflammatory effect of PGE2 has not been elucidated definitively. The aim of this study was to identify the EP receptor by which PGE2 inhibits cytokine generation from human lung macrophages. This was determined by using recently-developed EP receptor ligands. Experimental approach: The effects of PGE2 and EP-selective agonists on lipopolysaccharide (LPS) induced tumour necrosis factor-α (TNFα) and interleukin-6 (IL-6) generation from macrophages were evaluated. The effects of EP2-selective (PF-04852946, PF-04418948) and EP4-selective (L-161,982, CJ-042794) antagonists on PGE2 responses were studied. The expression of EP receptor subtypes by human lung macrophages was determined by RT-PCR. Key results: PGE2 inhibited LPS-induced and Streptococcus pneumoniae-induced cytokine generation from human lung macrophages. Analysis of mRNA levels indicated that macrophages expressed EP2 and EP4 receptors. L-902,688 (EP4-selective agonist) was considerably more potent than butaprost (EP2-selective agonist) as an inhibitor of TNFα generation from macrophages. EP2-selective antagonists had marginal effects on the PGE2 inhibition of TNFα generation whereas EP4-selective antagonists caused rightward shifts in the PGE2 concentration-response curves. Conclusions and implications: These studies demonstrate that the EP4 receptor is the principal receptor that mediates the anti-inflammatory effects of PGE2 on human lung macrophages. This suggests that EP4 agonists could be effective anti-inflammatory agents in human lung disease.