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, Shuh Narumiya

Research output: Contribution to journalArticlepeer-review

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.
Original languageEnglish
Pages (from-to)1685
JournalNature Communications
Volume4
DOIs
Publication statusPublished - 2013

Keywords

  • Animals
  • Cell Differentiation
  • Cyclic AMP
  • Dinoprostone
  • Interleukin-12
  • Mice
  • Mice, Inbred C57BL
  • Phosphatidylinositol 3-Kinases
  • Receptors, Antigen, T-Cell
  • Signal Transduction
  • Th1 Cells

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