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Prostaglandin E2 promotes Th1 differentiation via synergistic amplification of IL-12 signalling by cAMP and PI3-kinase

Author

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  • Chengcan Yao

    (Kyoto University Faculty of Medicine
    Core Research for Evolutional Science and Technology (CREST), Japan Science and Technology Agency (JST)
    Present address: MRC Centre for Inflammation Research, Queen’s Medical Research Institute, University of Edinburgh, Edinburgh EH16 4TJ, United Kingdom)

  • Takako Hirata

    (Kyoto University Faculty of Medicine
    Core Research for Evolutional Science and Technology (CREST), Japan Science and Technology Agency (JST))

  • Kitipong Soontrapa

    (Kyoto University Faculty of Medicine)

  • Xiaojun Ma

    (Kyoto University Faculty of Medicine)

  • Hiroshi Takemori

    (Laboratory of Cell Signaling and Metabolic Disease, National Institute of Biomedical Innovation)

  • Shuh Narumiya

    (Kyoto University Faculty of Medicine
    Core Research for Evolutional Science and Technology (CREST), Japan Science and Technology Agency (JST))

Abstract

T helper 1 (Th1) cells have critical roles in various autoimmune and proinflammatory diseases. cAMP has long been believed to act as a suppressor of IFN-γ production and Th1 cell-mediated immune inflammation. Here we show that cAMP actively promotes Th1 differentiation by inducing gene expression of cytokine receptors involved in this process. PGE2 signalling through EP2/EP4 receptors mobilizes the cAMP-PKA pathway, which induces CREB- and its co-activator CRTC2-mediated transcription of IL-12Rβ2 and IFN-γR1. Meanwhile, cAMP-mediated suppression of T-cell receptor signalling is overcome by simultaneous activation of PI3-kinase through EP2/EP4 and/or CD28. Loss of EP4 in T cells restricts expression of IL-12Rβ2 and IFN-γR1, and attenuates Th1 cell-mediated inflammation in vivo. These findings clarify the molecular mechanisms and pathological contexts of cAMP-mediated Th1 differentiation and have clinical and therapeutic implications for deployment of cAMP modulators as immunoregulatory drugs.

Suggested Citation

  • Chengcan Yao & Takako Hirata & Kitipong Soontrapa & Xiaojun Ma & Hiroshi Takemori & Shuh Narumiya, 2013. "Prostaglandin E2 promotes Th1 differentiation via synergistic amplification of IL-12 signalling by cAMP and PI3-kinase," Nature Communications, Nature, vol. 4(1), pages 1-15, June.
    • Handle: RePEc:nat:natcom:v:4:y:2013:i:1:d:10.1038_ncomms2684
    DOI: 10.1038/ncomms2684
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    Cited by:

    1. Matteo Villa & David E. Sanin & Petya Apostolova & Mauro Corrado & Agnieszka M. Kabat & Carmine Cristinzio & Annamaria Regina & Gustavo E. Carrizo & Nisha Rana & Michal A. Stanczak & Francesc Baixauli, 2024. "Prostaglandin E2 controls the metabolic adaptation of T cells to the intestinal microenvironment," Nature Communications, Nature, vol. 15(1), pages 1-19, December.

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