Prostaglandin E 2 suppresses allergic sensitization and lung inflammation by targeting the E prostanoid 2 receptor on T cells

Background— Endogenous prostanoids have been suggested to modulate sensitization during experimental allergic asthma, but the specific role of prostaglandin E 2 (PGE 2 ) or of specific E prostanoid (EP) receptors is not known. Objective— Here we tested the role of EP2 signaling in allergic asthma. Methods— Wild type (WT) and EP2−/− mice were subjected to ovalbumin sensitization and acute airway challenge. The PGE 2 analog misoprostol was administered during sensitization in both genotypes. In vitro culture of splenocytes and of 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. Results— As compared to 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 a stable PGE 2 analog during sensitization inhibited allergic inflammation. PGE 2 decreased cytokine production and inhibited STAT6 phosphorylation by CD3/CD28-stimulated CD4 pos T cells. Co-culture of flow cytometry-sorted splenic CD4 pos T cells and CD11c pos 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 pos EP2−/− T cells caused greater cytokine production in the lungs of WT mice than did transfer of WT CD4 pos T cells. Conclusion— We conclude that the PGE 2 -EP2 axis is an important endogenous brake on allergic airway inflammation, primarily targets T cells, and its agonism represents a potential novel therapeutic approach to asthma. study, we sought to specifically interrogate the role of the PGE 2 -EP2 axis in controlling sensitization and polarization in a model Our data support an important suppressive role for PGE in and further identify on as mediating 2 of