Anti-inflammatory effects of PGE2 in the lung: role of the EP4 receptor subtype

Thorax. 2015 Aug;70(8):740-7. doi: 10.1136/thoraxjnl-2014-206592. Epub 2015 May 4.


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 (EP1-4) 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 EP1-3) 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.

Keywords: Asthma Mechanisms; Asthma Pharmacology; COPD Pharmacology.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Asthma / drug therapy*
  • Asthma / metabolism
  • Asthma / pathology
  • Cells, Cultured
  • Disease Models, Animal
  • Female
  • Humans
  • Lung / drug effects
  • Lung / metabolism*
  • Lung / pathology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Receptors, Prostaglandin E / therapeutic use*
  • Receptors, Prostaglandin E, EP4 Subtype / metabolism*


  • Ptger4 protein, mouse
  • Receptors, Prostaglandin E
  • Receptors, Prostaglandin E, EP4 Subtype