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Suppression of allergic inflammation by the prostaglandin E receptor subtype EP3

Nature Immunology volume 6, pages 524–531 (2005)Cite this article

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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Figure 1: Enhanced allergic responses in Ptger3−/− mice.
Figure 2: Enhanced inflammatory cell infiltration in the lungs of Ptger3−/− mice.
Figure 3: Suppression of airway inflammation by an EP3 agonist.
Figure 4: Inhibition by the EP3 agonist of antigen-induced mediator release.
Figure 5: Effects of OVA challenge and the EP3 agonist on gene expression in the lungs.
Figure 6: Localization of EP3 and CCL17 in the lungs.

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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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Author notes

  1. Tomonori Kunikata, Hana Yamane, Eri Segi and Toshiyuki Matsuoka: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Pharmacology and Faculty of Medicine and Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto, 606-8501, Japan

    Tomonori Kunikata, Eri Segi, Toshiyuki Matsuoka & Shuh Narumiya

  2. Department of Physiological Chemistry, Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto, 606-8501, Japan

    Hana Yamane, Yukihiko Sugimoto, Satoshi Tanaka & Atsushi Ichikawa

  3. Department of Pharmacology, Gifu Pharmaceutical University, Gifu, 502-0003, Japan

    Hiroyuki Tanaka & Hiroichi Nagai

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  1. Tomonori Kunikata
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Correspondence to Shuh Narumiya.

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Competing interests

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.

Supplementary information

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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