The Signaling Pathway of PGE2 and Its Regulatory Role in T Cell Differentiation

An, Yang; Yao, Jiameng; Niu, Xiaoyin

doi:10.1155/2021/9087816

Cited by 18 publications

(5 citation statements)

References 58 publications

(59 reference statements)

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“…As the expression of CD73 can be induced by PGE2 on macrophages [ 25 ] and PGE2 is a well-known regulator of T cell differentiation and plasticity [ 26 ], we first verified if adult SC could produce PGE2. First, analysis of mRNA expression of the inducible form of cyclooxygenase (COX-2), the major enzymes in prostaglandin production, revealed that SC express COX-2 mRNA and its level in SC could be significantly up to three-fold up-regulated by SC pre-exposure to the melanoma-conditioned medium ( Figure 2 A).…”

Section: Resultsmentioning

confidence: 99%

Tumor-Induced T Cell Polarization by Schwann Cells

Shurin

Vats

Kruglov

et al. 2022

Cells

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Nerve-cancer crosstalk resulting in either tumor neurogenesis or intratumoral neurodegeneration is critically controlled by Schwann cells, the principal glial cells of the peripheral nervous system. Though the direct stimulating effect of Schwann cells on malignant cell proliferation, motility, epithelial–mesenchymal transition, and the formation of metastases have been intensively investigated, the ability of Schwann cells to affect the effector and regulatory immune cells in the tumor environment is significantly less studied. Here, we demonstrated that tumor cells could stimulate Schwann cells to produce high levels of prostaglandin E, which could be blocked by COX-2 inhibitors. This effect was mediated by tumor-derived TGF-β as neutralization of this cytokine in the tumor-conditioned medium completely blocked the inducible prostaglandin E production by Schwann cells. Similar protective effects were also induced by the Schwann cell pretreatment with TGF-βR1/ALK4/5/7 and MAPK/ERK kinase inhibitors of the canonical and non-canonical TGF-β signaling pathways, respectively. Furthermore, prostaglandin E derived from tumor-activated Schwann cells blocked the proliferation of CD3/CD28-activated T cells and upregulated the expression of CD73 and PD-1 on both CD4+ and CD8+ T cells, suggesting T cell polarization to the exhausted phenotype. This new pathway of tumor-induced T cell inhibition via the activation of neuroglial cells represents new evidence of the importance of nerve–cancer crosstalk in controlling tumor development and progression. A better understanding of the tumor-neuro-immune axis supports the development of efficient targets for harnessing this axis and improving the efficacy of cancer therapy.

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Section: Resultsmentioning

confidence: 99%

Tumor-Induced T Cell Polarization by Schwann Cells

Shurin

Vats

Kruglov

et al. 2022

Cells

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“…Previous studies have demonstrated that PGE2 regulates the activation, maturation, differentiation, migration, and other activities of immune cells. 7 , 17 For example, PGE2 reduces the production of interleukin (IL)‐12 in monocytes or dendritic, which selectively prevents the differentiation of naïve CD4 + T cells into Th1 cells. 18 , 19 Chen et al showed that PGE2 suppressed the function of antigen‐specific CD8 + T cells and promoted the apoptosis of CD8 + T cells.…”

Section: Discussionmentioning

confidence: 99%

“…Although PGE2 has a short half‐life, it has a key role in mediating inflammation and a variety of biological processes in vivo. Previous studies have demonstrated that PGE2 regulates the activation, maturation, differentiation, migration, and other activities of immune cells 7,17 . For example, PGE2 reduces the production of interleukin (IL)‐12 in monocytes or dendritic, which selectively prevents the differentiation of naïve CD4 + T cells into Th1 cells 18,19 .…”

Section: Discussionmentioning

confidence: 99%

PGE2 inhibits neutrophil phagocytosis through the EP2R–cAMP–PTEN pathway

Wang

Wei

et al. 2022

Immunity Inflam & Disease

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Prostaglandin E2 (PGE2) is a potent lipid mediator of inflammation that modulates immune cell function by binding to unique G protein‐coupled receptors (EP receptors). PGE2 production increases during microbial infection and inflammation. In this study, we assessed the effect of PGE2 on the phagocytosis of bacteria by neutrophils, which are key players during infection and inflammation. We also looked for specific EP receptor signaling pathways that contributed to the neutrophil phagocytic activity. PGE2 (50–1000 ng/ml) inhibited the phagocytosis of Escherichia coli by HL‐60 human neutrophils in a concentration‐dependent manner. Inhibition of neutrophil phagocytosis by PGE2 correlated with increased intracellular cyclic adenosine monophosphate (cAMP) production, and forskolin, an adenosyl cyclase agonist, confirmed the inhibitory effect of cAMP stimulation on neutrophil phagocytosis. The expression of EP2 receptors by HL‐60 cells was confirmed by western blot analysis, and selective agonism of EP2 receptors mimicked the inhibition of phagocytosis by PGE2. The EP2 receptor antagonist AH‐6089 partially blocked the inhibition of neutrophil phagocytosis PGE2. Specific inhibition of phosphatase and tensin homolog (PTEN) enzyme attenuated the inhibition of neutrophil phagocytosis by PGE2, and both PGE2 and increased intracellular cAMP increased neutrophil PTEN activity, which was associated with decreased PTEN phosphorylation. The results support negative regulation of the antimicrobial activity of neutrophils (i.e., phagocytosis), which has important implications for the future management of bacterial infections.

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“…PGE 2 exerts its biological activity mainly through four recognized receptors (EP1-EP4) [ 22 ]. From those receptors, EP2 and EP4 have been shown to possess immunosuppressive effects, enhancing the cAMP-PKA signaling pathway [ 23 ].…”

Section: Discussionmentioning

confidence: 99%

Human Amniotic Membrane Mesenchymal Stem Cell-Synthesized PGE2 Exerts an Immunomodulatory Effect on Neutrophil Extracellular Trap in a PAD-4-Dependent Pathway through EP2 and EP4

Estúa-Acosta

Buentello-Volante

Magaña‐Guerrero

et al. 2022

Cells

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Human amniotic membrane mesenchymal stem cells (hAM-MSC) secrete a myriad of components with immunosuppressive activities. In the present research, we aimed to describe the effect of prostaglandin E2 (PGE2) secreted by hAM-MSCs on neutrophil extracellular trap (NET) release and to characterize the role of its receptors (EP2/EP4) in PAD-4 and NFkB activity in neutrophils. Human peripheral blood neutrophils were ionomycin-stimulated in the presence of hAM-MSC conditioned medium (CM) treated or not with the selective PGE2 inhibitor MF-63, PGE2, EP2/EP4 agonists, and the selective PAD-4 inhibitor GSK-484. NET release, PAD-4, and NFkB activation were analyzed. Ionomycin induced NET release, which was inhibited in the presence of hAM-MSC-CM, while CM from hAM-MSCs treated with MF-63 prevented NET release inhibition. PGE2 and EP2/EP4 agonists, and GSK-484 inhibited NET release. EP2/EP4 agonists and GSK-484 inhibited H3-citrullination but did not affect PAD-4 protein expression. Finally, PGE2 and EP2/EP4 agonists and GSK-484 increased NFkB phosphorylation. Taken together, these results suggest that hAM-MSC exert their immunomodulatory activities through PGE2, inhibiting NET release in a PAD-4-dependent pathway. This research proposes a new mechanism by which hAM-MSC exert their activities when modulating the innate immune response and inhibiting NET release.

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The Signaling Pathway of PGE2 and Its Regulatory Role in T Cell Differentiation

Cited by 18 publications

References 58 publications

Tumor-Induced T Cell Polarization by Schwann Cells

Tumor-Induced T Cell Polarization by Schwann Cells

PGE2 inhibits neutrophil phagocytosis through the EP2R–cAMP–PTEN pathway

Human Amniotic Membrane Mesenchymal Stem Cell-Synthesized PGE2 Exerts an Immunomodulatory Effect on Neutrophil Extracellular Trap in a PAD-4-Dependent Pathway through EP2 and EP4

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