Prostaglandin E₂ Promotes Th1 Differentiation Via Synergistic Amplification of IL-12 Signalling by CAMP and PI3-kinase

Overview

Journal Nat Commun

Specialty Biology

Date 2013 Apr 12

PMID 23575689

Citations 54

Authors

Chengcan Yao

Takako Hirata

Kitipong Soontrapa

Xiaojun Ma

Hiroshi Takemori

Shuh Narumiya

Affiliations

Soon will be listed here.

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.

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