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

Authors:
Yao C1, Hirata T, Soontrapa K, Ma X, Takemori H, Narumiya S.
In:
Source: Nat Commun.
Publication Date: (2013)
Issue: 4: 1685
Research Area:
Immunotherapy / Hematology
Cells used in publication:
T cell, mouse - C57BL/6
Species: mouse
Tissue Origin: blood
T cell, mouse, stim
Species: mouse
Tissue Origin: blood
Platform:
4D-Nucleofector™ X-Unit
Experiment
Fresh isolated mouse CD4+-T-cells were transfected with 500 pmol siRNA using Amaxa P3 Primary Cell 4D-Nucloefector Kit X with the programm DN-100 in 100 µl volume Cells were directly transferred into full RPMI1640, then were cultured and stimulated in the presence of IL-7. CD4+ T-cells from SIK2-minus mouse (derived from C57BL) have been stimulated for 2 days with anti-CD3 and anti-CD28, then rest on ice for 1-2 h followed by tranfection with 5 µg Plasmid in 100 µl reaction using P3 Primary Cell 4D-Nulceofector Kit and program EO-115.
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-? 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-12Rß2 and IFN-?R1. 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-12Rß2 and IFN-?R1, 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.