Prostaglandin E2-induced IL-23p19 Subunit Is Regulated by cAMP-responsive Element-binding Protein and C/AATT Enhancer-binding Protein β in Bone Marrow-derived Dendritic Cells

Kocieda, Virginia; Adhikary, Sabina; Emig, Frances A.; Yen, Jui‐Hung; Toscano, Miguel G.; Ganea, Doina

doi:10.1074/jbc.m112.402958

Cited by 43 publications

(42 citation statements)

References 54 publications

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“…It is different than the recent report by the Ganea's group, which found in their BMDCs that PGE 2 amplifies LPS-induced Il23a expression by mobilizing both cAMP-PKA-CREB and cAMP-Epac-C/EBPb pathways. 25 Another difference between the studies is that Ganea's group consistently found that the PGE 2 action was exerted through both EP2 and EP4 receptors in their BMDCs, whereas our BMDCs utilize only EP4. As shown in the RESULTS section, our BMDCs expressed EP2 mRNA at a level comparable to EP4 but did not respond to an EP2 agonist that showed potent actions in T cells in an EP2-dependent manner.…”

Section: Discussionmentioning

confidence: 80%

“…This may have been because of mouse strain or preparation procedures; we used C57BL/6 mice as our source and Ganea's group used B10.A mice. 25 Previously, Nishigaki et al found different sensitivities of EP2 and EP4 to PGE 2 -induced desensitization. 27 Although that paper reported that EP4 undergoes desensitization more quickly than does EP2, which was the opposite of our finding, it showed that different sensitivities to desensitization do occur between EP2 and EP4.…”

Section: Discussionmentioning

confidence: 95%

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Prostaglandin E2-EP4 signaling persistently amplifies CD40-mediated induction of IL-23 p19 expression through canonical and non-canonical NF-κB pathways

Aoki

Narumiya

2015

Cell Mol Immunol

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While there is mounting evidence that interleukin (IL)-23-IL-17 axis plays a critical role in the pathogenesis of various autoimmune diseases, much remains to be elucidated on how IL-23 is induced in the pathological processes. IL-23 is a heterodimer composed of p19 and p40, the latter being shared with IL-12. We previously reported that prostaglandin (PG) E 2 promotes CD40-mediated induction of Il23a (p19) expression through its E receptor subtype 4 (EP4) receptor in splenic dendritic cells (DCs). Here, we have analyzed signaling pathways regulating Il23a induction in the cross talk between EP4 and CD40 in bone marrow-derived DCs. We found that PGE 2 synergistically induced Il23a transcription with CD40 signaling. An EP4 agonist, but not agonists of EP1, EP2, or EP3, reproduced this action. Stimulation of CD40 with an agonist antibody evoked biphasic induction of Il23a expression, with the early phase peaking at 1 h and the late phase peaking at 12 h and lasting up to 36 h after stimulation, whereas induction by lipopolysaccharide or tumor necrosis factor-a was transient. The early phase induction by CD40 stimulation was absent in DCs derived from Nfkb1-deficient mice, and the late phase induction was eliminated by RNA interference of nuclear factor-kappa B (NF-kB) p100 subunit. Further, cAMP response element-binding protein (CREB) depletion completely eliminated the induction of Il23a by CD40 stimulation. The addition of the EP4 agonist amplified the induction in both phases through the cAMP-protein kinase A (PKA) pathway. These results suggest that Il23a expression in DCs is synergistically triggered by the PG E 2 -EP4-cAMP-PKA pathway and canonical/non-canonical NF-kB pathways and CREB activated by CD40 stimulation. Cellular & Molecular Immunology

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Section: Discussionmentioning

confidence: 80%

Section: Discussionmentioning

confidence: 95%

Prostaglandin E2-EP4 signaling persistently amplifies CD40-mediated induction of IL-23 p19 expression through canonical and non-canonical NF-κB pathways

Aoki

Narumiya

2015

Cell Mol Immunol

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“…The latter can be phosphorylated via EPAC. EPAC (via C/AATT enhancer-binding protein b) and phospho-CREB were shown to stimulate p19 transcriptional activity (22). Accordingly, we were able to show that a specific EPAC activator (8-CPT-2Me-cAMP) induced increased IL-23 production in LPS-DC (Supplemental Fig.…”

Section: Idc Express Functional B 2 Armentioning

confidence: 73%

Norepinephrine Controls Effector T Cell Differentiation through β2-Adrenergic Receptor–Mediated Inhibition of NF-κB and AP-1 in Dendritic Cells

Takenaka

Araújo

Maricato

et al. 2016

The Journal of Immunology

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Despite accumulating evidence indicating that neurotransmitters released by the sympathetic nervous system can modulate the activity of innate immune cells, we still know very little about how norepinephrine impacts signaling pathways in dendritic cells (DC) and the consequence of that in DC-driven T cell differentiation. In this article, we demonstrate that β2-adrenergic receptor (β2AR) activation in LPS-stimulated DC does not impair their ability to promote T cell proliferation; however, it diminishes IL-12p70 secretion, leading to a shift in the IL-12p70/IL-23 ratio. Although β2AR stimulation in DC induces protein kinase A–dependent cAMP-responsive element–binding protein phosphorylation, the effect of changing the profile of cytokines produced upon LPS challenge occurs in a protein kinase A–independent manner and, rather, is associated with inhibition of the NF-κB and AP-1 signaling pathways. Moreover, as a consequence of the inverted IL-12p70/IL-23 ratio following β2AR stimulation, LPS-stimulated DC promoted the generation of CD4+ T cells that, upon TCR engagement, produced lower amounts of IFN-γ and higher levels of IL-17. These findings provide new insights into molecular and cellular mechanisms by which β2AR stimulation in murine DC can influence the generation of adaptive immune responses and may explain some aspects of how sympathetic nervous system activity can modulate immune function.

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“…However, the actual involvement of prostaglandin E 2 as an autocrine mediator has not been proved unambiguously. For instance, COX inhibition by a high concentration of indomethacin showed a weak inhibitory effect (7). A note of caution regarding the straightforward translation of the results on il23a transcription to the overall production of IL-23 arises from the possible influence of concomitant factors such as the parallel production of the IL-12/23 p40 chain and il23a mRNA stability (60).…”

Section: Discussionmentioning

confidence: 99%

The Unfolded Protein Response and the Phosphorylations of Activating Transcription Factor 2 in the trans-Activation of il23a Promoter Produced by β-Glucans

Rodríguez

Domingo

Alonso

et al. 2014

Journal of Biological Chemistry

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Background: Phagocytosis and Th17 immune response control fungal invasion. Results: ␤-Glucans mobilize nuclear C/EBP homologous protein (CHOP) and increase activating transcription factor 2 (ATF2) binding to the il23a promoter. Conclusion: ␤-Glucans direct proapoptotic CHOP to phagosomal vesicles and induce ATF2-dependent il23a transcription. Significance: The mechanisms underlying the unfolded protein response and the trans-activation of il23a elicited by ␤-glucans are ascertained.

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Prostaglandin E2-induced IL-23p19 Subunit Is Regulated by cAMP-responsive Element-binding Protein and C/AATT Enhancer-binding Protein β in Bone Marrow-derived Dendritic Cells

Cited by 43 publications

References 54 publications

Prostaglandin E2-EP4 signaling persistently amplifies CD40-mediated induction of IL-23 p19 expression through canonical and non-canonical NF-κB pathways

Prostaglandin E2-EP4 signaling persistently amplifies CD40-mediated induction of IL-23 p19 expression through canonical and non-canonical NF-κB pathways

Norepinephrine Controls Effector T Cell Differentiation through β2-Adrenergic Receptor–Mediated Inhibition of NF-κB and AP-1 in Dendritic Cells

The Unfolded Protein Response and the Phosphorylations of Activating Transcription Factor 2 in the trans-Activation of il23a Promoter Produced by β-Glucans

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