@article {Birrell740, author = {Mark A Birrell and Sarah A Maher and Bilel Dekkak and Victoria Jones and Sissie Wong and Peter Brook and Maria G Belvisi}, title = {Anti-inflammatory effects of PGE2 in the lung: role of the EP4 receptor subtype}, volume = {70}, number = {8}, pages = {740--747}, year = {2015}, doi = {10.1136/thoraxjnl-2014-206592}, publisher = {BMJ Publishing Group Ltd}, abstract = {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 (EP1{\textendash}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 EP1{\textendash}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.}, issn = {0040-6376}, URL = {https://thorax.bmj.com/content/70/8/740}, eprint = {https://thorax.bmj.com/content/70/8/740.full.pdf}, journal = {Thorax} }