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

Chengcan Yao, Takako Hirata, Kitipong Soontrapa, Xiaojun Ma, Hiroshi Takemori and Shuh Narumiya ()
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Chengcan Yao: Kyoto University Faculty of Medicine
Takako Hirata: Kyoto University Faculty of Medicine
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

Nature Communications, 2013, vol. 4, issue 1, 1-15

Abstract: 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.

Date: 2013
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DOI: 10.1038/ncomms2684

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