Receptors for prostaglandin E2 that regulate cellular immune responses in the mouse

Nataraj, Chandra; Thomas, Dennis W.; Tilley, Stephen L.; Nguyen, MyTrang; Mannon, Roslyn B.; Koller, Beverly H.; Coffman, Thomas M.

doi:10.1172/jci200113640

Cited by 258 publications

(91 citation statements)

References 32 publications

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“…In vitro evidence for a role for the EP2 receptor in antigen presentation has been reported by Nataraj et al (13), who found a decrease in the ability of PGE 2 to inhibit EP2 -/-macrophage in stimulating an allogeneic MLR. We have confirmed and extended this MLR finding with purified DCs.…”

mentioning

confidence: 82%

Cancer-associated immunodeficiency and dendritic cell abnormalities mediated by the prostaglandin EP2 receptor

Yang¹,

Yamagata²,

Yadav³

et al. 2003

J. Clin. Invest.

208

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IntroductionTumor-induced immune suppression is a fundamental problem in cancer biology and immunotherapy. COX metabolites act as tumor promoters when overproduced (1-3), and recent studies have demonstrated that the COX metabolite prostaglandin E 2 (PGE 2 ) exhibits potent immunosuppressive effects, orchestrating an imbalance between type 1 and type 2 cytokines (4-6). PGE 2 mediates its effects, in part, through G proteincoupled PGE receptors, designated EP1, EP2, EP3, and EP4. Differential expression of these EP receptors mediate the diverse, and often antagonistic, effects of PGE 2 and its analogues on a variety of cell types (7-9). The EP2 receptor regulates the activation and differentiation of mouse B lymphocytes (10), modulates T cell development (11-12), and regulates macrophage cytokine release (13) and postsurgery immune responses (14). The EP2 receptor also plays a key role in the differentiation of macrophage-like osteoclast cells as well as the functional response of osteoclasts to PGE 2 (15). Importantly, PGE 2 has been shown to be a key modulator of DC function, altering cytokine production as well as the I-A d class II cell surface marker (16)(17). Despite data describing the production of PGE 2 by tumors and the expression of the EP2 receptor in specific immune populations, the role of the EP2 receptor in modulation of the host immune response to tumors remains uncharacterized.Previous studies show that COX-2 and PGE 2 can play important roles in tumor angiogenesis (3,18,19). Recent publications show that in Apc ∆716 mice, a mouse model for human familial adenomatous polyposis, homozygous deletion of the gene encoding EP2 decreases the number and size of intestinal polyps through inhibition of tumor angiogenesis (19,20). In this study we determined the role of the EP2 receptor in host-tumor interactions. Unlike the results observed in the Apc ∆716 model, we observed no effect of the disruption of the EP2 receptor on tumor angiogenesis. We then examined the role of the EP2 receptor in T cell function, as well as DC differentiation, and functional responses to tumor challenge. Our data demonstrate an important role for the EP2

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mentioning

confidence: 82%

Cancer-associated immunodeficiency and dendritic cell abnormalities mediated by the prostaglandin EP2 receptor

Yang¹,

Yamagata²,

Yadav³

et al. 2003

J. Clin. Invest.

208

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“…Receptors EP1–4, associated with different intracellular signaling pathways, are responsible for mediating the cellular effects of PGE2 [70]. The inhibition of the Th1 cell proliferation is dependent on EP2 [108]. The EP2 and perhaps the EP4 receptors mediate the suppressive effects of PGE2 on T-cells [109].…”

Section: Inflammatory Cells and Cancer Cell Biomarkersmentioning

confidence: 99%

A Comparative Approach of Tumor-Associated Inflammation in Mammary Cancer between Humans and Dogs

Carvalho

Silva-Carvalho

Pires

et al. 2016

BioMed Research International

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Infiltrating cells of the immune system are widely accepted to be generic constituents of tumor microenvironment. It has been well established that the development of mammary cancer, both in humans and in dogs, is associated with alterations in numbers and functions of immune cells at the sites of tumor progression. These tumor infiltrating immune cells seem to exhibit exclusive phenotypic and functional characteristics and mammary cancer cells can take advantage of signaling molecules released by them. Cancer related inflammation has an important role in mammary carcinogenesis, contributing to the acquisition of core hallmark capabilities that allow cancer cells to survive, proliferate, and disseminate. Indeed, recent studies in human breast cancer and in canine mammary tumors have identified a growing list of signaling molecules released by inflammatory cells that serve as effectors of their tumor-promoting actions. These include the COX-2, the tumor EGF, the angiogenic VEGF, other proangiogenic factors, and a large variety of chemokines and cytokines that amplify the inflammatory state. This review describes the intertwined signaling pathways shared by T-lymphocytic/macrophage infiltrates and important tissue biomarkers in both human and dog mammary carcinogenesis.

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“…In the case of the EP3 receptor, three main isoforms of this receptor exist – EP3 α, β, and γ – and they can signal through different G proteins, but it appears that the major pathway is through G i , which leads to decreased intracellular cAMP levels. Messenger RNA for all the different PGE 2 receptors, with the exception of the EP3 α and β isoforms, is present in murine splenic T cells (Nataraj et al, 2001). In naive T cells isolated from peripheral blood, EP2 and EP4 receptors appear to be the most abundant and are upregulated in response to activation (Boniface et al, 2009).…”

Section: Biosynthesis Of and Signaling By Eicosanoids In T Lymphocytesmentioning

confidence: 99%

“…An anti-proliferative effect is also well documented. Through the EP2 (Nataraj et al, 2001) and possibly the EP4 (Kabashima et al, 2002) receptor, PGE 2 can inhibit T cell proliferation in CD4+ and CD8+ cells (Goodwin et al, 1977; Hendricks et al, 2000). It has also been shown that PGE 2 inhibits the proliferation of double-negative Tregs (Lee et al, 2009).…”

Section: Biosynthesis Of and Signaling By Eicosanoids In T Lymphocytesmentioning

confidence: 99%

Proinflammatory and Immunoregulatory Roles of Eicosanoids in T Cells

Lone¹,

Taskén²

2013

Front. Immunol.

112

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Eicosanoids are inflammatory mediators primarily generated by hydrolysis of membrane phospholipids by phospholipase A2 to ω-3 and ω-6 C20 fatty acids that next are converted to leukotrienes (LTs), prostaglandins (PGs), prostacyclins (PCs), and thromboxanes (TXAs). The rate-limiting and tightly regulated lipoxygenases control synthesis of LTs while the equally well-controlled cyclooxygenases 1 and 2 generate prostanoids, including PGs, PCs, and TXAs. While many of the classical signs of inflammation such as redness, swelling, pain, and heat are caused by eicosanoid species with vasoactive, pyretic, and pain-inducing effects locally, some eicosanoids also regulate T cell functions. Here, we will review eicosanoid production in T cell subsets and the inflammatory and immunoregulatory functions of LTs, PGs, PCs, and TXAs in T cells.

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Receptors for prostaglandin E2 that regulate cellular immune responses in the mouse

Cited by 258 publications

References 32 publications

Cancer-associated immunodeficiency and dendritic cell abnormalities mediated by the prostaglandin EP2 receptor

Cancer-associated immunodeficiency and dendritic cell abnormalities mediated by the prostaglandin EP2 receptor

A Comparative Approach of Tumor-Associated Inflammation in Mammary Cancer between Humans and Dogs

Proinflammatory and Immunoregulatory Roles of Eicosanoids in T Cells

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