Abstract
Prostaglandins, including PGD2 and PGE2, are produced during allergic reactions. Although PGD2 is an important mediator of allergic responses, aspirin-like drugs that inhibit prostaglandin synthesis are generally ineffective in allergic disorders, suggesting that another prostaglandin-mediated pathway prevents the development of allergic reactions. Here we show that such a pathway may be mediated by PGE2 acting at the prostaglandin E receptor EP3. Mice lacking EP3 developed allergic inflammation that was much more pronounced than that in wild-type mice or mice deficient in other prostaglandin E receptor subtypes. Conversely, an EP3-selective agonist suppressed the inflammation. This suppression was effective when the agonist was administered 3 h after antigen challenge and was associated with inhibition of allergy-related gene expression. Thus, the PGE2-EP3 pathway is an important negative modulator of allergic reactions.
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Acknowledgements
We thank ONO Pharmaceutical for prostaglandin E receptor–selective compounds; T. Fujiwara for animal care; T. Arai and Y. Kitagawa for help in preparation of the manuscript; and S. Matsui for help in statistical analyses. Supported in part by the Program for the Promotion of Fundamental Studies in Health Sciences of the Pharmaceuticals and Medical Devices Agency of Japan; Grants-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science, and Technology of Japan; and ONO Research Foundation.
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This work was supported in part by ONO Pharmaceutical, which has a patent on the use of an EP3 agonist as a therapeutic agent for allergic inflammation.
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Supplementary Table 1
Genes which are increased by allergen and suppressed by the EP3 agonist more than 6 out of 9 pairs (195 genes, Cluster 1) (XLS 138 kb)
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Kunikata, T., Yamane, H., Segi, E. et al. Suppression of allergic inflammation by the prostaglandin E receptor subtype EP3. Nat Immunol 6, 524–531 (2005). https://doi.org/10.1038/ni1188
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DOI: https://doi.org/10.1038/ni1188
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