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mPGES-1-Mediated Production of PGE and EP4 Receptor Sensing Regulate T Cell Colonic Inflammation.
Maseda D, Banerjee A, Johnson EM, Washington MK, Kim H, Lau KS, Crofford LJ
(2018) Front Immunol 9: 2954
MeSH Terms: Animals, CD4-Positive T-Lymphocytes, Colitis, Dinoprostone, Intestinal Mucosa, Mice, Inbred C57BL, Mice, Knockout, Mice, Transgenic, Nuclear Receptor Subfamily 1, Group F, Member 3, Prostaglandin-E Synthases, Receptors, Prostaglandin E, EP2 Subtype, Receptors, Prostaglandin E, EP4 Subtype, T-Lymphocytes, T-Lymphocytes, Regulatory
Show Abstract · Added March 25, 2020
PGE is a lipid mediator of the initiation and resolution phases of inflammation, as well as a regulator of immune system responses to inflammatory events. PGE is produced and sensed by T cells, and autocrine or paracrine PGE can affect T cell phenotype and function. In this study, we use a T cell-dependent model of colitis to evaluate the role of PGE on pathological outcome and T-cell phenotypes. CD4 T effector cells either deficient in mPGES-1 or the PGE receptor EP4 are less colitogenic. Absence of T cell autocrine mPGES1-dependent PGE reduces colitogenicity in association with an increase in CD4RORγt cells in the lamina propria. In contrast, recipient mice deficient in mPGES-1 exhibit more severe colitis that corresponds with a reduced capacity to generate FoxP3 T cells, especially in mesenteric lymph nodes. Thus, our research defines how mPGES-1-driven production of PGE by different cell types in distinct intestinal locations impacts T cell function during colitis. We conclude that PGE has profound effects on T cell phenotype that are dependent on the microenvironment.
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MeSH Terms
mPGES1-Dependent Prostaglandin E (PGE) Controls Antigen-Specific Th17 and Th1 Responses by Regulating T Autocrine and Paracrine PGE Production.
Maseda D, Johnson EM, Nyhoff LE, Baron B, Kojima F, Wilhelm AJ, Ward MR, Woodward JG, Brand DD, Crofford LJ
(2018) J Immunol 200: 725-736
MeSH Terms: Animals, Autocrine Communication, Dinoprostone, Epitopes, T-Lymphocyte, Gene Expression Regulation, Immunization, Immunomodulation, Lymphocyte Activation, Mice, Paracrine Communication, Phenotype, Prostaglandin-E Synthases, Receptors, Prostaglandin E, EP2 Subtype, Receptors, Prostaglandin E, EP4 Subtype, Th1 Cells, Th17 Cells
Show Abstract · Added March 25, 2020
The integration of inflammatory signals is paramount in controlling the intensity and duration of immune responses. Eicosanoids, particularly PGE, are critical molecules in the initiation and resolution of inflammation and in the transition from innate to acquired immune responses. Microsomal PGE synthase 1 (mPGES1) is an integral membrane enzyme whose regulated expression controls PGE levels and is highly expressed at sites of inflammation. PGE is also associated with modulation of autoimmunity through altering the IL-23/IL-17 axis and regulatory T cell (Treg) development. During a type II collagen-CFA immunization response, lack of mPGES1 impaired the numbers of CD4 regulatory (Treg) and Th17 cells in the draining lymph nodes. Ag-experienced mPGES1 CD4 cells showed impaired IL-17A, IFN-γ, and IL-6 production when rechallenged ex vivo with their cognate Ag compared with their wild-type counterparts. Additionally, production of PGE by cocultured APCs synergized with that of Ag-experienced CD4 T cells, with mPGES1 competence in the APC compartment enhancing CD4 IL-17A and IFN-γ responses. However, in contrast with CD4 cells that were Ag primed in vivo, exogenous PGE inhibited proliferation and skewed IL-17A to IFN-γ production under Th17 polarization of naive T cells in vitro. We conclude that mPGES1 is necessary in vivo to mount optimal Treg and Th17 responses during an Ag-driven primary immune response. Furthermore, we uncover a coordination of autocrine and paracrine mPGES1-driven PGE production that impacts effector T cell IL-17A and IFN-γ responses.
Copyright © 2018 by The American Association of Immunologists, Inc.
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Efferocytosis-induced prostaglandin E2 production impairs alveolar macrophage effector functions during Streptococcus pneumoniae infection.
Salina AC, Souza TP, Serezani CH, Medeiros AI
(2017) Innate Immun 23: 219-227
MeSH Terms: Animals, Apoptosis, Bacteriolysis, Cyclic AMP, Cyclic AMP-Dependent Protein Kinases, Dinoprostone, Female, Homeostasis, Humans, Hydrogen Peroxide, Jurkat Cells, Macrophages, Alveolar, Phagocytosis, Pneumococcal Infections, Rats, Rats, Wistar, Receptors, Prostaglandin E, EP2 Subtype, Receptors, Prostaglandin E, EP4 Subtype, Signal Transduction, Streptococcus pneumoniae
Show Abstract · Added May 4, 2017
Alveolar macrophages (AMs) are multitasking cells that maintain lung homeostasis by clearing apoptotic cells (efferocytosis) and performing antimicrobial effector functions. Different PRRs have been described to be involved in the binding and capture of non-opsonized Streptococcus pneumoniae, such as TLR-2, mannose receptor (MR) and scavenger receptors (SRs). However, the mechanism by which the ingestion of apoptotic cells negatively influences the clearance of non-opsonized S. pneumoniae remains to be determined. In this study, we evaluated whether the prostaglandin E2 (PGE) produced during efferocytosis by AMs inhibits the ingestion and killing of non-opsonized S. pneumoniae. Resident AMs were pre-treated with an E prostanoid (EP) receptor antagonist, inhibitors of cyclooxygenase and protein kinase A (PKA), incubated with apoptotic Jurkat T cells, and then challenged with S. pneumoniae. Efferocytosis slightly decreased the phagocytosis of S. pneumoniae but greatly inhibited bacterial killing by AMs in a manner dependent on PGE production, activation of the EP2-EP4/cAMP/PKA pathway and inhibition of HO production. Our data suggest that the PGE produced by AMs during efferocytosis inhibits HO production and impairs the efficient clearance non-opsonized S. pneumoniae by EP2-EP4/cAMP/PKA pathway.
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20 MeSH Terms
Opposing roles of LTB4 and PGE2 in regulating the inflammasome-dependent scorpion venom-induced mortality.
Zoccal KF, Sorgi CA, Hori JI, Paula-Silva FW, Arantes EC, Serezani CH, Zamboni DS, Faccioli LH
(2016) Nat Commun 7: 10760
MeSH Terms: Animals, Arachidonate 5-Lipoxygenase, Blotting, Western, Carrier Proteins, Celecoxib, Cyclic AMP, Cyclic AMP-Dependent Protein Kinases, Cyclooxygenase Inhibitors, Dinoprostone, In Vitro Techniques, Indoles, Indomethacin, Inflammasomes, Interleukin-1beta, Leukotriene B4, Lipoxygenase Inhibitors, Macrophages, Macrophages, Peritoneal, Mice, Mice, Knockout, NF-kappa B, NLR Family, Pyrin Domain-Containing 3 Protein, Phosphoproteins, Prostaglandin Antagonists, Receptors, Prostaglandin E, EP2 Subtype, Receptors, Prostaglandin E, EP4 Subtype, Reverse Transcriptase Polymerase Chain Reaction, Scorpion Stings, Scorpion Venoms, Scorpions, Xanthones
Show Abstract · Added May 4, 2017
Tityus serrulatus sting causes thousands of deaths annually worldwide. T. serrulatus-envenomed victims exhibit local or systemic reaction that culminates in pulmonary oedema, potentially leading to death. However, the molecular mechanisms underlying T. serrulatus venom (TsV) activity remain unknown. Here we show that TsV triggers NLRP3 inflammasome activation via K(+) efflux. Mechanistically, TsV triggers lung-resident cells to release PGE2, which induces IL-1β production via E prostanoid receptor 2/4-cAMP-PKA-NFκB-dependent mechanisms. IL-1β/IL-1R actions account for oedema and neutrophil recruitment to the lungs, leading to TsV-induced mortality. Inflammasome activation triggers LTB4 production and further PGE2 via IL-1β/IL-1R signalling. Activation of LTB4-BLT1/2 pathway decreases cAMP generation, controlling TsV-induced inflammation. Exogenous administration confirms LTB4 anti-inflammatory activity and abrogates TsV-induced mortality. These results suggest that the balance between LTB4 and PGE2 determines the amount of IL-1β inflammasome-dependent release and the outcome of envenomation. We suggest COX1/2 inhibition as an effective therapeutic intervention for scorpion envenomation.
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31 MeSH Terms
EP4 and EP2 receptor activation of protein kinase A by prostaglandin E2 impairs macrophage phagocytosis of Clostridium sordellii.
Rogers LM, Thelen T, Fordyce K, Bourdonnay E, Lewis C, Yu H, Zhang J, Xie J, Serezani CH, Peters-Golden M, Aronoff DM
(2014) Am J Reprod Immunol 71: 34-43
MeSH Terms: Cell Line, Clostridium Infections, Clostridium sordellii, Cyclic AMP, Cyclic AMP-Dependent Protein Kinases, Dinoprostone, Humans, Immune Tolerance, Immunity, Innate, Macrophages, Phagocytosis, Protein Isoforms, Receptors, Prostaglandin E, EP2 Subtype, Receptors, Prostaglandin E, EP4 Subtype
Show Abstract · Added May 4, 2017
PROBLEM - Clostridium sordellii causes endometrial infections, but little is known regarding host defenses against this pathogen.
METHOD OF STUDY - We tested the hypothesis that the immunoregulatory lipid prostaglandin (PG) E2 suppresses human macrophage clearance of C. sordellii through receptor-induced increases in intracellular cyclic adenosine monophosphate (cAMP). The THP-1 macrophage cell line was used to quantify C. sordellii phagocytosis.
RESULTS - PGE2 increased cAMP levels, activated protein kinase A (PKA), and inhibited the class A scavenger receptor-dependent phagocytosis of C. sordellii. Activation of the EP2 and EP4 receptors increased intracellular cAMP and inhibited phagocytosis, with evidence favoring a more important role for EP4 over EP2. This was supported by EP receptor expression data and the use of pharmacological receptor antagonists. In addition, the PKA isoform RI appeared to be more important than RII in mediating the suppression of ingestion of C. sordellii.
CONCLUSION - The endogenous lipid mediator PGE2 impairs human innate immune responses against C. sordellii.
© 2013 John Wiley & Sons Ltd.
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14 MeSH Terms
An important role of prostanoid receptor EP2 in host resistance to Mycobacterium tuberculosis infection in mice.
Kaul V, Bhattacharya D, Singh Y, Van Kaer L, Peters-Golden M, Bishai WR, Das G
(2012) J Infect Dis 206: 1816-25
MeSH Terms: Animals, CD4-Positive T-Lymphocytes, Disease Models, Animal, Forkhead Transcription Factors, Gene Expression, Gene Expression Profiling, Immunophenotyping, Interleukin-2 Receptor alpha Subunit, Mice, Mice, Inbred C57BL, Mycobacterium tuberculosis, Receptors, Prostaglandin E, EP2 Subtype, T-Lymphocytes, Regulatory, Tuberculosis
Show Abstract · Added March 20, 2014
Mycobacterium tuberculosis, the causative agent of tuberculosis, resides and replicates within susceptible hosts by inhibiting host antimicrobial mechanisms. Prostaglandin E(2) (PGE(2)), produced by M. tuberculosis-infected macrophages, exerts a variety of immunomodulatory functions via 4 receptors (EP1-EP4), each mediating distinct PGE(2) functions. Here, we show that M. tuberculosis infection selectively upregulates EP2 messenger RNA expression in CD4(+) T cells. We found that EP2 deficiency in mice increases susceptibility to M. tuberculosis infection, which correlated with reduced antigen-specific T-cell responses and increased levels of CD4(+)CD25(+)Foxp3(+) T-regulatory cells. These findings have revealed an important role for EP2 in host immune defense against tuberculosis. As a G protein-coupled receptor, EP2 could serve as a target for immunotherapy of tuberculosis.
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14 MeSH Terms
Prostaglandin E2 deficiency uncovers a dominant role for thromboxane A2 in house dust mite-induced allergic pulmonary inflammation.
Liu T, Laidlaw TM, Feng C, Xing W, Shen S, Milne GL, Boyce JA
(2012) Proc Natl Acad Sci U S A 109: 12692-7
MeSH Terms: Allergens, Animals, Antigens, Dermatophagoides, Asthma, Dinoprostone, Intercellular Adhesion Molecule-1, Intramolecular Oxidoreductases, Male, Mice, Mice, Knockout, Pneumonia, Prostaglandin-E Synthases, Pulmonary Eosinophilia, Receptors, Prostaglandin E, EP1 Subtype, Receptors, Prostaglandin E, EP2 Subtype, Receptors, Thromboxane, Signal Transduction, Thromboxane A2, Up-Regulation
Show Abstract · Added March 26, 2014
Prostaglandin E(2) (PGE(2)) is an abundant lipid inflammatory mediator with potent but incompletely understood anti-inflammatory actions in the lung. Deficient PGE(2) generation in the lung predisposes to airway hyperresponsiveness and aspirin intolerance in asthmatic individuals. PGE(2)-deficient ptges(-/-) mice develop exaggerated pulmonary eosinophilia and pulmonary arteriolar smooth-muscle hyperplasia compared with PGE(2)-sufficient controls when challenged intranasally with a house dust mite extract. We now demonstrate that both pulmonary eosinophilia and vascular remodeling in the setting of PGE(2) deficiency depend on thromboxane A(2) and signaling through the T prostanoid (TP) receptor. Deletion of TP receptors from ptges(-/-) mice reduces inflammation, vascular remodeling, cytokine generation, and airway reactivity to wild-type levels, with contributions from TP receptors localized to both hematopoietic cells and tissue. TP receptor signaling ex vivo is controlled heterologously by E prostanoid (EP)(1) and EP(2) receptor-dependent signaling pathways coupling to protein kinases C and A, respectively. TP-dependent up-regulation of intracellular adhesion molecule-1 expression is essential for the effects of PGE(2) deficiency. Thus, PGE(2) controls the strength of TP receptor signaling as a major bronchoprotective mechanism, carrying implications for the pathobiology and therapy of asthma.
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19 MeSH Terms
Prostanoid receptor 2 signaling protects T helper 2 cells from BALB/c mice against activation-induced cell death.
Kaul V, Van Kaer L, Das G, Das J
(2012) J Biol Chem 287: 25434-9
MeSH Terms: Animals, Cell Death, Cell Survival, Dinoprostone, Female, Lymphocyte Activation, Mice, Mice, Inbred BALB C, Prostaglandin Endoperoxides, Receptors, Prostaglandin E, EP2 Subtype, Signal Transduction, Th2 Cells
Show Abstract · Added March 20, 2014
T helper 2 (Th2) cells play a central role in the progression of many diseases such as allergic airway inflammation, autoimmune diseases, and infections caused by intracellular pathogens. Consequently, animals such as BALB/c mice, which exhibit a propensity for generating Th2 responses, are susceptible to allergic airway inflammation, type-II autoimmune diseases, and various infections induced by intracellular pathogens, namely, Leishmania. In contrast, C3H/OuJ mice have a tendency for generating T helper 1 (Th1) responses and show resistance to these diseases. Here, we show that prostaglandin endoperoxide E(2) selectively inhibits activation-induced cell death of Th2 cells by signaling through its receptor E-prostanoid receptor 2 (EP2). Consequently, Th2 cells derived from BALB/c mice expressed very high levels of EP2. On the other hand, Th2 cells derived from C3H/OuJ mice expressed very low levels of EP2, which failed to support the survival of Th2 cells. Furthermore, we found that this effect of EP2 on Th2 cells from BALB/c mice was executed by a granzyme B-mediated mechanism. EP2 belongs to a group of G-protein-coupled receptors that are amenable to therapeutic targeting. Our findings therefore identify EP2 as a promising target for small molecule-directed immunomodulation.
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12 MeSH Terms
A study of prostaglandin pathway genes and interactions with current nonsteroidal anti-inflammatory drug use in colorectal adenoma.
Edwards TL, Shrubsole MJ, Cai Q, Li G, Dai Q, Rex DK, Ulbright TM, Fu Z, Murff HJ, Smalley W, Ness R, Zheng W
(2012) Cancer Prev Res (Phila) 5: 855-63
MeSH Terms: Adenoma, Aged, Anti-Inflammatory Agents, Non-Steroidal, Case-Control Studies, Colonic Polyps, Colorectal Neoplasms, Cyclooxygenase 2, Female, Genotyping Techniques, Humans, Hydroxyprostaglandin Dehydrogenases, Male, Middle Aged, Polymorphism, Single Nucleotide, Receptors, Prostaglandin E, EP2 Subtype, Receptors, Prostaglandin E, EP3 Subtype, Receptors, Prostaglandin E, EP4 Subtype, Risk Factors, Signal Transduction
Show Abstract · Added March 5, 2014
Colorectal cancer (CRC) is the second leading cause of cancer-related death and usually arises from colorectal polyps. Screening and removal of polyps reduce mortality from CRC. Colorectal polyps are known to aggregate in families; however the genetic determinants for risk of polyps are unknown. In addition, it has been shown that nonsteroidal anti-inflammatory drug (NSAID) use decreases the risk of CRC and the incidence and size of polyps. In this study, we used data from the Tennessee Colorectal Polyp Study and the Tennessee-Indiana Adenoma Recurrence Study to evaluate selected genes from the prostaglandin (PG) metabolism and signaling pathways for association with risk of polyps and for interactions with NSAIDs. Our design consisted of discovery and replication phases for a total of 2,551 Caucasian polyp cases and 3,285 Caucasian controls. We carried out multivariable logistic regression to test for association in both the discovery and replication phase and further examined the results with meta-analysis. We detected association signals in the genes PGE receptor 3 (PTGER3) and 15-hydroxyprostaglandin dehydrogenase (HPGD), both strong biologic candidates for influence on polyp risk. We did not observe the previously reported effects and effect modification in PG-endoperoxide synthase 2 (PTGS2), PGE receptor 2 (PTGER2), or PGE receptor 4 (PTGER4), although we did observe a single nucleotide polymorphism in PTGER2 associated with risk of multiple adenomas. We also observed effect modification of the HPGD signal by NSAID exposure.
©2012 AACR.
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19 MeSH Terms
PTEN directly activates the actin depolymerization factor cofilin-1 during PGE2-mediated inhibition of phagocytosis of fungi.
Serezani CH, Kane S, Medeiros AI, Cornett AM, Kim SH, Marques MM, Lee SP, Lewis C, Bourdonnay E, Ballinger MN, White ES, Peters-Golden M
(2012) Sci Signal 5: ra12
MeSH Terms: Actins, Animals, Candida albicans, Candidiasis, Cells, Cultured, Cofilin 1, Cyclic AMP, Cyclic AMP-Dependent Protein Kinase Type I, Cyclic AMP-Dependent Protein Kinase Type II, Dinoprostone, Female, Immune Tolerance, Macrophages, Alveolar, PTEN Phosphohydrolase, Phagocytosis, Phosphorylation, Rats, Rats, Wistar, Receptors, Prostaglandin E, EP2 Subtype, Receptors, Prostaglandin E, EP4 Subtype
Show Abstract · Added May 4, 2017
Macrophage ingestion of the yeast Candida albicans requires its recognition by multiple receptors and the activation of diverse signaling programs. Synthesis of the lipid mediator prostaglandin E(2) (PGE(2)) and generation of cyclic adenosine monophosphate (cAMP) also accompany this process. Here, we characterized the mechanisms underlying PGE(2)-mediated inhibition of phagocytosis and filamentous actin (F-actin) polymerization in response to ingestion of C. albicans by alveolar macrophages. PGE(2) suppressed phagocytosis and F-actin formation through the PGE(2) receptors EP2 and EP4, cAMP, and activation of types I and II protein kinase A. Dephosphorylation and activation of the actin depolymerizing factor cofilin-1 were necessary for these inhibitory effects of PGE(2). PGE(2)-dependent activation of cofilin-1 was mediated by the protein phosphatase activity of PTEN (phosphatase and tensin homolog deleted on chromosome 10), with which it directly associated. Because enhanced production of PGE(2) accompanies many immunosuppressed states, the PTEN-dependent pathway described here may contribute to impaired antifungal defenses.
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20 MeSH Terms