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 E₂ (PGE₂) 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 PGE₂ 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 EP₄ (Ptger4^−/−) receptors had higher levels of airway inflammation, suggesting that endogenous PGE₂ was suppressing inflammation via EP₄ receptor activation. Cell-based assay systems (murine and human monocytes/alveolar macrophages) demonstrated that PGE₂ inhibited cytokine release from LPS-stimulated cells and that this was mimicked by an EP₄ (but not EP_1–3) receptor agonist and inhibited by an EP₄ 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 EP₄ receptor activation is responsible for the anti-inflammatory activity of PGE₂ in a range of disease relevant models and, as such, could represent a novel therapeutic target for chronic airway inflammatory conditions.