Essential role of EP3 subtype in prostaglandin E<sub>2</sub>-induced adhesion of mouse cultured and peritoneal mast cells to the Arg-Gly-Asp-enriched matrix

Sakanaka, Mariko; Tanaka, Satoshi; Sugimoto, Yukihiko; Ichikawa, Atsushi

doi:10.1152/ajpcell.00218.2008

Cited by 14 publications

(12 citation statements)

References 28 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…These results indicate that PGE 2 -EP3-mediated vascular hyperpermeability depends on MCs. Indeed, we found that the EP3 receptor is abundantly expressed in BMMCs, as reported previously (38 ). After 5 wk, reconstitution and maturation of the transferred MCs in ear tissues were confirmed by monitoring gene expression of MC-specific genes (Supplemental Fig.…”

Section: Pge 2 -Induced Vascular Hyperpermeability Depends On Ep3 Recsupporting

confidence: 91%

See 1 more Smart Citation

Prostaglandin E2–EP3 Signaling Induces Inflammatory Swelling by Mast Cell Activation

Morimoto

Shirata

Taketomi

et al. 2014

The Journal of Immunology

Self Cite

124

View full text Add to dashboard Cite

PGE2 has long been known as a potentiator of acute inflammation, but its mechanisms of action still remain to be defined. In this study, we employed inflammatory swelling induced in mice by arachidonate and PGE2 as models and dissected the role and mechanisms of action of each EP receptor at the molecular level. Arachidonate- or PGE2-induced vascular permeability was significantly reduced in EP3-deficient mice. Intriguingly, the PGE2-induced response was suppressed by histamine H1 antagonist treatment, histidine decarboxylase deficiency, and mast cell deficiency. The impaired PGE2-induced response in mast cell–deficient mice was rescued upon reconstitution with wild-type mast cells but not with EP3-deficient mast cells. Although the number of mast cells, protease activity, and histamine contents in ear tissues in EP3-deficient mice were comparable to those in wild-type mice, the histamine contents in ear tissues were attenuated upon PGE2 treatment in wild-type but not in EP3-deficient mice. Consistently, PGE2–EP3 signaling elicited histamine release in mouse peritoneal and bone marrow–derived mast cells, and it exerted degranulation and IL-6 production in a manner sensitive to pertussis toxin and a PI3K inhibitor and dependent on extracellular Ca2+ ions. These results demonstrate that PGE2 triggers mast cell activation via an EP3–Gi/o–Ca2+ influx/PI3K pathway, and this mechanism underlies PGE2-induced vascular permeability and consequent edema formation.

show abstract

Section: Pge 2 -Induced Vascular Hyperpermeability Depends On Ep3 Recsupporting

confidence: 91%

“…To investigate the mechanism of PGE 2 -induced MC activation, we used mouse BMMCs in which EP3 is abundantly expressed (38). We first compared the basic characteristics of WT and Ptger3…”

Section: Pge 2 Triggers Not Only Degranulation But Also Il-6 Productimentioning

confidence: 99%

Prostaglandin E2–EP3 Signaling Induces Inflammatory Swelling by Mast Cell Activation

Morimoto

Shirata

Taketomi

et al. 2014

The Journal of Immunology

Self Cite

124

View full text Add to dashboard Cite

show abstract

“…PGE 2 elicits multiple biological responses in mast cells in vitro, for example, adhesion to basement membrane proteins, chemotaxis (17,42), and the production of chemokines (43) and eicosanoids (44), in addition to the up-regulation (37,48) and down-regulation (36, 44) of antigen-mediated mast cell degranulation and cytokine production. The extent and relevance of these responses to PGE 2 in a physiological setting are unclear.…”

Section: Discussionmentioning

confidence: 99%

“…mTORC2 Is Required for Optimal PGE 2 -induced PGD 2 and CCL2 Release-In addition to chemotaxis, PGE 2 has also been documented to induce adhesion of mast cells to basement membrane proteins, as well as the production of the chemokine, CCL2, and the eicosanoid, PGD 2 (42)(43)(44). We next determined whether mTORC2 played a role in these responses in addition to chemotaxis.…”

Section: Pge 2 -Induced Activation Of Mtor In Bmmcs Is Mediated By G␣mentioning

confidence: 99%

Prostaglandin E2 Activates and Utilizes mTORC2 as a Central Signaling Locus for the Regulation of Mast Cell Chemotaxis and Mediator Release

Kuehn

Jung

Beaven

et al. 2011

Journal of Biological Chemistry

View full text Add to dashboard Cite

Prostaglandin (PG) E 2 , a potent mediator produced in inflamed tissues, can substantially influence mast cell responses including adhesion to basement membrane proteins, chemotaxis, and chemokine production. However, the signaling pathways by which PGE 2 induces mast cell chemotaxis and chemokine production remains undefined. In this study, we identified the downstream target of phosphatidylinositol 3-kinase, mammalian target of rapamycin (mTOR), as a key regulator of these responses. In mouse bone marrow-derived mast cells, PGE 2 was found to induce activation of mTORC1 (mTOR complexed to raptor) as indicated by increased p70S6K and 4E-BP1 phosphorylation, and activation of mTORC2 (mTOR complexed to rictor), as indicated by increased phosphorylation of AKT at position Ser 473. Selective inhibition of the mTORC1 cascade by rapamycin or by the use of raptor-targeted shRNA failed to decrease PGE 2 -mediated chemotaxis or chemokine generation. However, inhibition of the mTORC2 cascade through the dual mTORC1/mTORC2 inhibitor Torin, or through rictor-targeted shRNA, resulted in a significant attenuation in PGE 2 -mediated chemotaxis, which was associated with a comparable decrease in actin polymerization. Furthermore, mTORC2 down-regulation decreased PGE 2 -induced production of the chemokine monocyte chemoattractant protein-1 (CCL2), which was linked to a significant reduction in ROS production. These findings are consistent with the conclusion that activation of mTORC2, downstream of PI3K, represents a critical signaling locus for chemotaxis and chemokine release from PGE 2 -activated mast cells.

show abstract

“…32 PGE 2 has been shown to stimulate chemotaxis and adhesion of MCs through EP. 33,34 In a recent report Morimoto et al 19 demonstrated that EP 3 signaling in MCs generated PGE 2 -induced vasodilatation and subsequent edema formation and speculated that EP 3 -mediated MC activation might be involved in antigen-independent innate immune reactions. Interestingly, we identified that the LTD 4 plus PGE 2 synergism is also EP 3 dependent, strengthening the idea that EP 3 activation might contribute to a proinflammatory role of PGE 2 .…”

Section: Discussionmentioning

confidence: 99%

Leukotriene D 4 and prostaglandin E 2 signals synergize and potentiate vascular inflammation in a mast cell–dependent manner through cysteinyl leukotriene receptor 1 and E-prostanoid receptor 3

Kondeti

Al‐Azzam

Duah

et al. 2016

Journal of Allergy and Clinical Immunology

View full text Add to dashboard Cite

Background Although arachidonic acid metabolites, cysteinyl leukotrienes (cys-LTs; leukotriene [LT] C4, LTD4, and LTE4), and prostaglandin (PG) E2 are generated at the site of inflammation, it is not known whether crosstalk exists between these 2 classes of inflammatory mediators. Objective We sought to determine the role of LTD4-PGE2 crosstalk in inducing vascular inflammation in vivo, identify effector cells, and ascertain specific receptors and pathways involved in vitro. Methods Vascular (ear) inflammation was assessed by injecting agonists into mouse ears, followed by measuring ear thickness and histology, calcium influx with Fura-2, phosphorylation and expression of signaling molecules by means of immunoblotting, PGD2 and macrophage inflammatory protein 1β generation by using ELISA, and expression of transcripts by using RT-PCR. Candidate receptors and signaling molecules were identified by using antagonists and inhibitors and confirmed by using small interfering RNA. Results LTD4 plus PGE2 potentiated vascular permeability and edema, gearing the system toward proinflammation in wild-type mice but not in KitW-sh mice. Furthermore, LTD4 plus PGE2, through cysteinyl leukotriene receptor 1 (CysLT1R) and E-prostanoid receptor (EP) 3, enhanced extracellular signal-regulated kinase (Erk) and c-fos phosphorylation, inflammatory gene expression, macrophage inflammatory protein 1β secretion, COX-2 upregulation, and PGD2 generation in mast cells. Additionally, we uncovered that this synergism is mediated through Gi, protein kinase G, and Erk signaling. LTD4 plus PGE2–potentiated effects are partially sensitive to CysLT1R or EP3 antagonists but completely abolished by simultaneous treatment both in vitro and in vivo. Conclusions Our results unravel a unique LTD4-PGE2 interaction affecting mast cells through CysLT1R and EP3 involving Gi, protein kinase G, and Erk and contributing to vascular inflammation in vivo. Furthermore, current results also suggest an advantage of targeting both CysLT1R and EP3 in attenuating inflammation.

show abstract

Essential role of EP3 subtype in prostaglandin E₂-induced adhesion of mouse cultured and peritoneal mast cells to the Arg-Gly-Asp-enriched matrix

Cited by 14 publications

References 28 publications

Prostaglandin E2–EP3 Signaling Induces Inflammatory Swelling by Mast Cell Activation

Prostaglandin E2–EP3 Signaling Induces Inflammatory Swelling by Mast Cell Activation

Prostaglandin E2 Activates and Utilizes mTORC2 as a Central Signaling Locus for the Regulation of Mast Cell Chemotaxis and Mediator Release

Leukotriene D 4 and prostaglandin E 2 signals synergize and potentiate vascular inflammation in a mast cell–dependent manner through cysteinyl leukotriene receptor 1 and E-prostanoid receptor 3

Contact Info

Product

Resources

About

Essential role of EP3 subtype in prostaglandin E2-induced adhesion of mouse cultured and peritoneal mast cells to the Arg-Gly-Asp-enriched matrix

Cited by 14 publications

References 28 publications

Prostaglandin E2–EP3 Signaling Induces Inflammatory Swelling by Mast Cell Activation

Prostaglandin E2–EP3 Signaling Induces Inflammatory Swelling by Mast Cell Activation

Prostaglandin E2 Activates and Utilizes mTORC2 as a Central Signaling Locus for the Regulation of Mast Cell Chemotaxis and Mediator Release

Leukotriene D 4 and prostaglandin E 2 signals synergize and potentiate vascular inflammation in a mast cell–dependent manner through cysteinyl leukotriene receptor 1 and E-prostanoid receptor 3

Contact Info

Product

Resources

About

Essential role of EP3 subtype in prostaglandin E₂-induced adhesion of mouse cultured and peritoneal mast cells to the Arg-Gly-Asp-enriched matrix