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

Yao C, Hirata T, Soontrapa K, Ma X, Takemori H, Narumiya S - Nat Commun (2013)

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacology, Kyoto University Faculty of Medicine, Kyoto 606 8501, Japan.

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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A model for synergistic action of cAMP and PI3K in Th1 differentiation.cAMP generated in response to PGE2 binding to EP2/EP4 activates PKA, which phosphorylates CREB and activates CRTC2 through phosphorylation of SIK. Activated CREB and CRTC2 translocate to the nucleus and induce expression of Il12rb2, Ifngr1 and possibly Il2rb, thus facilitating Th1 differentiation synergistically with IL-12, IFN-γ and IL-2. While cAMP-PKA inhibits T-cell activation by suppressing TCR signalling, coactivation of PI3K by EP2/EP4 and CD28 cancels this inhibition and promotes the Th1-facilitative action of cAMP.
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f8: A model for synergistic action of cAMP and PI3K in Th1 differentiation.cAMP generated in response to PGE2 binding to EP2/EP4 activates PKA, which phosphorylates CREB and activates CRTC2 through phosphorylation of SIK. Activated CREB and CRTC2 translocate to the nucleus and induce expression of Il12rb2, Ifngr1 and possibly Il2rb, thus facilitating Th1 differentiation synergistically with IL-12, IFN-γ and IL-2. While cAMP-PKA inhibits T-cell activation by suppressing TCR signalling, coactivation of PI3K by EP2/EP4 and CD28 cancels this inhibition and promotes the Th1-facilitative action of cAMP.

Mentions: Here we have demonstrated how cAMP signalling facilitates Th1 differentiation, and shown that PGE2-EP4 signalling is representative of such cAMP signalling operating in T cells. Figure 8 depicts our model for cAMP-mediated Th1 differentiation and its cross-talk with PI3K pathway in TCR activation. In addition to prostanoids, there are a number of other agents that can activate cAMP signalling in T cells, such as catecholamines, histamine and adenosine8. Our results suggest a possibility that these substances similarly facilitate Th1 differentiation and promote immune inflammation. This is particularly the case for those substances that activates both PI3K and cAMP signalling simultaneously. Given that most of these receptors are G-protein coupled receptors (GPCRs), our present results show how GPCR signalling cooperates with cytokine signalling, that is, amplifying the latter actions by inducing their receptors. We propose to designate such GPCR actions as cytokine amplification and ligands of such GPCR as cytokine amplifiers. This cytokine amplifying action of GPCR ligands surely accounts for some of their pathophysiological actions and may, therefore, be of therapeutic consideration.


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

Yao C, Hirata T, Soontrapa K, Ma X, Takemori H, Narumiya S - Nat Commun (2013)

A model for synergistic action of cAMP and PI3K in Th1 differentiation.cAMP generated in response to PGE2 binding to EP2/EP4 activates PKA, which phosphorylates CREB and activates CRTC2 through phosphorylation of SIK. Activated CREB and CRTC2 translocate to the nucleus and induce expression of Il12rb2, Ifngr1 and possibly Il2rb, thus facilitating Th1 differentiation synergistically with IL-12, IFN-γ and IL-2. While cAMP-PKA inhibits T-cell activation by suppressing TCR signalling, coactivation of PI3K by EP2/EP4 and CD28 cancels this inhibition and promotes the Th1-facilitative action of cAMP.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3644078&req=5

f8: A model for synergistic action of cAMP and PI3K in Th1 differentiation.cAMP generated in response to PGE2 binding to EP2/EP4 activates PKA, which phosphorylates CREB and activates CRTC2 through phosphorylation of SIK. Activated CREB and CRTC2 translocate to the nucleus and induce expression of Il12rb2, Ifngr1 and possibly Il2rb, thus facilitating Th1 differentiation synergistically with IL-12, IFN-γ and IL-2. While cAMP-PKA inhibits T-cell activation by suppressing TCR signalling, coactivation of PI3K by EP2/EP4 and CD28 cancels this inhibition and promotes the Th1-facilitative action of cAMP.
Mentions: Here we have demonstrated how cAMP signalling facilitates Th1 differentiation, and shown that PGE2-EP4 signalling is representative of such cAMP signalling operating in T cells. Figure 8 depicts our model for cAMP-mediated Th1 differentiation and its cross-talk with PI3K pathway in TCR activation. In addition to prostanoids, there are a number of other agents that can activate cAMP signalling in T cells, such as catecholamines, histamine and adenosine8. Our results suggest a possibility that these substances similarly facilitate Th1 differentiation and promote immune inflammation. This is particularly the case for those substances that activates both PI3K and cAMP signalling simultaneously. Given that most of these receptors are G-protein coupled receptors (GPCRs), our present results show how GPCR signalling cooperates with cytokine signalling, that is, amplifying the latter actions by inducing their receptors. We propose to designate such GPCR actions as cytokine amplification and ligands of such GPCR as cytokine amplifiers. This cytokine amplifying action of GPCR ligands surely accounts for some of their pathophysiological actions and may, therefore, be of therapeutic consideration.

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacology, Kyoto University Faculty of Medicine, Kyoto 606 8501, Japan.

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.

Show MeSH
Related in: MedlinePlus