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

ABSTRACT:

Background and purpose

PGE₂ inhibits cytokine generation from human lung macrophages. However, the EP receptor that mediates this beneficial anti-inflammatory effect of PGE₂ has not been defined. 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 LPS-induced generation of TNF-? 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 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 receptor-selective agonist) was considerably more potent than butaprost (EP₂ receptor-selective agonist) as an inhibitor of TNF-? generation from macrophages. EP₂ receptor-selective antagonists had marginal effects on the PGE₂ inhibition of TNF-? generation, whereas EP₄ receptor-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 receptor agonists could be effective anti-inflammatory agents in human lung disease.

SUBMITTER: Gill SK 

PROVIDER: S-EPMC5056231 | biostudies-literature | 2016 Nov

REPOSITORIES: biostudies-literature