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Prostaglandin E2–EP4 signaling promotes immune inflammation through TH1 cell differentiation and TH17 cell expansion

Abstract

Two distinct helper T (TH) subsets, TH1 and TH17, mediate tissue damage and inflammation in animal models of various immune diseases such as multiple sclerosis, rheumatoid arthritis, inflammatory bowel diseases and allergic skin disorders. These experimental findings, and the implication of these TH subsets in human diseases, suggest the need for pharmacological measures to manipulate these TH subsets. Here we show that prostaglandin E2 (PGE2) acting on its receptor EP4 on T cells and dendritic cells not only facilitates TH1 cell differentiation but also amplifies interleukin-23–mediated TH17 cell expansion in vitro. Administration of an EP4-selective antagonist in vivo decreases accumulation of both TH1 and TH17 cells in regional lymph nodes and suppresses the disease progression in mice subjected to experimental autoimmune encephalomyelitis or contact hypersensitivity. Thus, PGE2-EP4 signaling promotes immune inflammation through TH1 differentiation and TH17 expansion, and EP4 antagonism may be therapeutically useful for various immune diseases.

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Figure 1: PGE2 facilitates TH1 differentiation in vitro via EP2 and EP4.
Figure 2: EP2 and EP4 facilitate TH1 differentiation in vitro through PI3K signaling.
Figure 3: PGE2-EP4 signaling is required for IL-23 production by activated DCs.
Figure 4: PGE2 facilitates IL-23–induced TH17 expansion in vitro.
Figure 5: EP2 and EP4 facilitate IL-23–induced TH17 expansion in vitro through the cAMP-PKA pathway.
Figure 6: Suppression of in vivo differentiation and expansion of TH1 and TH17 cells by EP4 antagonist in CHS and EAE.

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Acknowledgements

We thank Ono Pharmaceutical Company for supplying EP agonists and EP4 antagonist. We also thank Q. Chen and M. Lamphier for information about their experiments, M. Hikida for cell sorting, T. Fujiwara for animal care and K. Nonomura and T. Arai for assistance. This work was supported in part by Grants-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology of Japan and by a grant from the National Institute of Biomedical Innovation of Japan.

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D.S., Y.S. and S.N. designed and discussed experiments; C.Y., D.S. and T.M. performed experiments on TH1 and TH17 differentiation and expansion; C.Y. and D.S. performed experiments on CHS; Y.E., Y.L. and D.S. performed experiments on EAE; C.Y., K.K. and Y.S. performed experiments on signaling; C.Y., D.S. and S.N. wrote the manuscript.

Corresponding author

Correspondence to Shuh Narumiya.

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Competing interests

This study was supported in part by a collaborative grant to Kyoto University from Ono Pharmaceuticals Company Ltd., which also partially funded the colonies of transgenic mice and provided EP agonists and an EP4 antagonist used in the study.

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Yao, C., Sakata, D., Esaki, Y. et al. Prostaglandin E2–EP4 signaling promotes immune inflammation through TH1 cell differentiation and TH17 cell expansion. Nat Med 15, 633–640 (2009). https://doi.org/10.1038/nm.1968

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