Endogenous prostanoids have been suggested to modulate sensitization during experimental allergic asthma, but the specific role of prostaglandin (PG) E₂ or of specific E prostanoid (EP) receptors is not known.

Here we tested the role of EP2 signaling in allergic asthma.

Wild-type (WT) and EP2^−/− mice were subjected to ovalbumin sensitization and acute airway challenge. The PGE₂ analog misoprostol was administered during sensitization in both genotypes. In vitro culture of splenocytes and flow-sorted dendritic cells and T cells defined the mechanism by which EP2 exerted its protective effect. Adoptive transfer of WT and EP2^−/− CD4 T cells was used to validate the importance of EP2 expression on T cells.

Compared with WT mice, EP2^−/− mice had exaggerated airway inflammation in this model. Splenocytes and lung lymph node cells from sensitized EP2^−/− mice produced more IL-13 than did WT cells, suggesting increased sensitization. In WT but not EP2^−/− mice, subcutaneous administration of misoprostol during sensitization inhibited allergic inflammation. PGE₂ decreased cytokine production and inhibited signal transducer and activator of transcription 6 phosphorylation by CD3/CD28-stimulated CD4⁺ T cells. Coculture of flow cytometry–sorted splenic CD4⁺ T cells and CD11c⁺ dendritic cells from WT or EP2^−/− mice suggested that the increased IL-13 production in EP2^−/− mice was due to the lack of EP2 specifically on T cells. Adoptive transfer of CD4⁺ EP2^−/− T cells caused greater cytokine production in the lungs of WT mice than did transfer of WT CD4⁺ T cells.

We conclude that the PGE₂-EP2 axis is an important endogenous brake on allergic airway inflammation and primarily targets T cells and that its agonism represents a potential novel therapeutic approach to asthma.