title: Prostaglandin E₂ promotes Th1 differentiation via synergistic amplification of IL-12 signalling by cAMP and PI3-kinase.
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.
authors.affiliation: Department of Pharmacology, Kyoto University Faculty of Medicine, Kyoto 606 8501, Japan.
authors.forename: Chengcan
authors.initials: C
authors.lastname: Yao
authors.forename: Takako
authors.initials: T
authors.lastname: Hirata
authors.forename: Kitipong
authors.initials: K
authors.lastname: Soontrapa
authors.forename: Xiaojun
authors.initials: X
authors.lastname: Ma
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Takemori
authors.forename: Shuh
authors.initials: S
authors.lastname: Narumiya
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000502:physiology*; D000242:Cyclic AMP / Q000502:physiology*; D015232:Dinoprostone / Q000502:physiology*; D018664:Interleukin-12 / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology*; D011948:Receptors, Antigen, T-Cell / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology*; D018417:Th1 Cells / Q000166:cytology*
chemical_list: D011948:Receptors, Antigen, T-Cell; D018664:Interleukin-12; D000242:Cyclic AMP; D019869:Phosphatidylinositol 3-Kinases; D015232:Dinoprostone