Anti-inflammatory effects of PGE(2) in the lung: role of the EP(4) receptor subtype

BACKGROUND: Asthma and chronic obstructive pulmonary disease (COPD) are chronic inflammatory diseases of the airway. Current treatment options (long acting β-adrenoceptor agonists and glucocorticosteroids) are not optimal as they are only effective in certain patient groups and safety concerns exist regarding both compound classes. Therefore, novel bronchodilator and anti-inflammatory strategies are being pursued. Prostaglandin E(2) (PGE(2)) is an arachidonic acid-derived eicosanoid produced by the lung which acts on four different G-protein coupled receptors (EP(1–4)) to cause an array of beneficial and deleterious effects. The aim of this study was to identify the EP receptor mediating the anti-inflammatory actions of PGE(2) in the lung using a range of cell-based assays and in vivo models. METHODS AND RESULTS: It was demonstrated in three distinct model systems (innate stimulus, lipopolysaccharide (LPS); allergic response, ovalbumin (OVA); inhaled pollutant, cigarette smoke) that mice missing functional EP(4) (Ptger4(−/−)) receptors had higher levels of airway inflammation, suggesting that endogenous PGE(2) was suppressing inflammation via EP(4) receptor activation. Cell-based assay systems (murine and human monocytes/alveolar macrophages) demonstrated that PGE(2) inhibited cytokine release from LPS-stimulated cells and that this was mimicked by an EP(4) (but not EP(1–3)) receptor agonist and inhibited by an EP(4) receptor antagonist. The anti-inflammatory effect occurred at the transcriptional level and was via the adenylyl cyclase/cAMP/ cAMP-dependent protein kinase (PKA) axis. CONCLUSION: This study demonstrates that EP(4) receptor activation is responsible for the anti-inflammatory activity of PGE(2) in a range of disease relevant models and, as such, could represent a novel therapeutic target for chronic airway inflammatory conditions.