The anti-inflammatory effects of PGE on human lung macrophages are mediated by the EP receptor.

Background And Purpose: PGE inhibits cytokine generation from human lung macrophages. However, the EP receptor that mediates this beneficial anti-inflammatory effect of PGE has not been defined. The aim of this study was to identify the EP receptor by which PGE inhibits cytokine generation from human lung macrophages. This was determined by using recently developed EP receptor ligands.

Experimental Approach: The effects of PGE and EP-selective agonists on LPS-induced generation of TNF-α and IL-6 from macrophages were evaluated. The effects of EP -selective (PF-04852946, PF-04418948) and EP -selective (L-161,982, CJ-042794) receptor antagonists on PGE responses were studied. The expression of EP receptor subtypes by human lung macrophages was determined by RT-PCR.

Key Results: PGE inhibited LPS-induced and Streptococcus pneumoniae-induced cytokine generation from human lung macrophages. Analysis of mRNA levels indicated that macrophages expressed EP and EP receptors. L-902,688 (EP receptor-selective agonist) was considerably more potent than butaprost (EP receptor-selective agonist) as an inhibitor of TNF-α generation from macrophages. EP receptor-selective antagonists had marginal effects on the PGE inhibition of TNF-α generation, whereas EP receptor-selective antagonists caused rightward shifts in the PGE concentration-response curves.

Conclusions And Implications: These studies demonstrate that the EP receptor is the principal receptor that mediates the anti-inflammatory effects of PGE on human lung macrophages. This suggests that EP receptor agonists could be effective anti-inflammatory agents in human lung disease.