Suppression of allergic inflammation by the prostaglandin E receptor subtype EP3

Kunikata, Tomonori; Yamane, Haruki; Segi, Eri; Matsuoka, Toshifumi; Sugimoto, Yukihiko; Tanaka, Satoshi; Tanaka, Hiroyuki; Nagai, Hiroichi; Ichikawa, Atsushi; Narumiya, Shuh

doi:10.1038/ni1188

Cited by 213 publications

(210 citation statements)

References 41 publications

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“…S2E). Notably, the absence of EP 3 , but not EP 2 receptors, potentiated airway eosinophilia in a previous study (48). The differences between that study and ours may relate to different allergens (Df vs. ovalbumin) and routes of sensitization (intranasal vs. intraperitoneal).The modest response of ptger2 −/− mice to Lys-ASA (Fig.…”

Section: Deletion Of Hematopoietic Ep 2 Receptors Partially Reproducecontrasting

confidence: 43%

Prostaglandin E₂deficiency causes a phenotype of aspirin sensitivity that depends on platelets and cysteinyl leukotrienes

Liu

Laidlaw

Katz

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

108

105

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Aspirin-exacerbated respiratory disease (AERD) is characterized by asthma, tissue eosinophilia, overproduction of cysteinyl leukotrienes (cysLTs), and respiratory reactions to nonselective cyclooxygenase (COX) inhibitors. Ex vivo studies suggest that functional abnormalities of the COX-2/microsomal prostaglandin (PG)E 2 synthase-1 system may underlie AERD. We demonstrate that microsomal PGE 2 synthase-1 null mice develop a remarkably AERD-like phenotype in a model of eosinophilic pulmonary inflammation. Lysine aspirin (Lys-ASA)-challenged PGE 2 synthase-1 null mice exhibit sustained increases in airway resistance, along with lung mast cell (MC) activation and cysLT overproduction. A stable PGE 2 analog and a selective E prostanoid (EP) 2 receptor agonist blocked the responses to Lys-ASA by ∼90%; EP 3 and EP 4 agonists were also active. The increases in airway resistance and MC products were blocked by antagonists of the type 1 cysLT receptor or 5-lipoxygenase, implying that bronchoconstriction and MC activation were both cysLT dependent. Lys-ASA-induced cysLT generation and MC activation depended on platelet-adherent granulocytes and T-prostanoid (TP) receptors. Thus, lesions that impair the inducible generation of PGE 2 remove control of platelet/granulocyte interactions and TP-receptor-dependent cysLT production, permitting MC activation in response to COX-1 inhibition. The findings suggest applications of antiplatelet drugs or TP receptor antagonists for the treatment of AERD.A spirin-exacerbated respiratory disease (AERD) affects 5-10% of all adults with asthma (1-3), ∼30% with severe asthma (4), and ∼40% with refractory chronic hyperplastic sinusitis (5). It involves severe eosinophilic respiratory tract inflammation and is defined by bronchoconstriction following the ingestion of nonselective COX inhibitors (6). Cysteinyl leukotrienes (cysLTs) (LTC 4 , LTD 4 , and LTE 4 ) drive these reactions, as well as some of the chronic features of AERD (7,8). CysLTs derive from arachidonic acid metabolized by 5-lipoxygenase (5-LO) to LTA 4 , conjugated to reduced glutathione by leukotriene C 4 synthase (LTC 4 S) to LTC 4 in mast cells (MCs), eosinophils, basophils, macrophages, and granulocyte-platelet complexes (9). After export, LTC 4 is converted sequentially to LTD 4 and LTE 4 . CysLTs induce bronchoconstriction (10, 11), tissue eosinophilia (12), and remodeling (13) through G-protein-coupled receptors (GPCRs) expressed by structural and hematopoietic cells (14-16). Individuals with AERD display higher urinary levels of LTE 4 than do aspirin-tolerant asthmatic (ATA) control subjects (17). Reactions to aspirin or other nonselective COX inhibitors are accompanied by marked further increases in urinary levels of LTE 4 and can be blocked by pretreatment with the 5-LO inhibitor zileuton or with antagonists of the type 1 receptor for cysLTs (CysLT 1 R) (18,19). The dependency on COX products to maintain homeostasis over 5-LO activity is a unique feature of AERD. Remarkably, subjects with AERD can tolerate selective ant...

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Section: Deletion Of Hematopoietic Ep 2 Receptors Partially Reproducecontrasting

confidence: 43%

Prostaglandin E₂deficiency causes a phenotype of aspirin sensitivity that depends on platelets and cysteinyl leukotrienes

Liu

Laidlaw

Katz

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

108

105

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“…PTGER3 encodes EP3, one of four receptors for prostaglandin E2, which has many biological functions, including inhibition of gastric acid secretion, inhibition of sodium and water reabsorption in kidney, uterine contractions, fever in response to exogenous and endogenous stimuli, and modulation of neurotransmitter release in central and peripheral neurons. 40 Mice lacking Ep3 have a mild, complex phenotype, including an impaired febrile response, 41 an impaired response of adrenocorticotropic hormone to bacterial endotoxin, 42 exaggerated allergic inflammation, 43 obesity, increased motor activity 44 and increased survival to bacterial infection. 45 PTGER3 is expressed as at least nine multiple splicing variants that have identical ligand binding properties but interact with different second messengers.…”

Section: Discussionmentioning

confidence: 99%

Prospective diagnostic analysis of copy number variants using SNP microarrays in individuals with autism spectrum disorders

et al. 2013

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Copy number variants (CNVs) have repeatedly been found to cause or predispose to autism spectrum disorders (ASDs). For diagnostic purposes, we screened 194 individuals with ASDs for CNVs using Illumina SNP arrays. In several probands, we also analyzed candidate genes located in inherited deletions to unmask autosomal recessive variants. Three CNVs, a de novo triplication of chromosome 15q11-q12 of paternal origin, a deletion on chromosome 9p24 and a de novo 3q29 deletion, were identified as the cause of the disorder in one individual each. An autosomal recessive cause was considered possible in two patients: a homozygous 1p31.1 deletion encompassing PTGER3 and a deletion of the entire DOCK10 gene associated with a rare hemizygous missense variant. We also identified multiple private or recurrent CNVs, the majority of which were inherited from asymptomatic parents. Although highly penetrant CNVs or variants inherited in an autosomal recessive manner were detected in rare cases, our results mainly support the hypothesis that most CNVs contribute to ASDs in association with other CNVs or point variants located elsewhere in the genome. Identification of these genetic interactions in individuals with ASDs constitutes a formidable challenge.

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“…PGE 2 is generally considered a proinflammatory mediator, and there is a clear relationship between disease activity and levels of PGE 2 in the tissue. PGE 2 also has antiinflammatory effects; for example, it can be broncho-protective in the lung (23), and stimulation of the PGE 2 receptor EP3 suppressed allergic inflammation in mouse (24). Because of these opposing effects, it is difficult to predict the role of individual eicosanoids in disease models in vivo based on the action of cyclooxygenase inhibitors that suppress PG production.…”

Section: Discussionmentioning

confidence: 99%

Chemotactic action of prostaglandin E₂on mouse mast cells acting via the PGE₂receptor 3

Weller

Collington

Hartnell

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

119

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Mast cells are long-lived cells that are principally recognized for their effector function in helminth infections and allergic reactions. These cells are derived from pluripotential hematopoietic stem cells in the bone marrow that give rise to committed mast cell progenitors in the blood and are recruited to tissues, where they mature. Little is known about the chemotactic signals responsible for recruitment of progenitors and localization of mature mast cells. A mouse model was set up to identify possible mast cell progenitor chemoattractants produced during repeated allergen challenge in vivo. After the final challenge, the nasal mucosa was removed to produce conditioned medium, which was tested in chemotaxis assays against 2-wk murine bone marrow-derived c-kit ؉ mast cells (BMMC). A single peak of chemotactic activity was seen on reverse-phase HPLC with a retention time and electrospray mass spectrum consistent with prostaglandin E 2 (PGE2). This lipid was found to be a highly potent chemoattractant for immature (2-wk) and also mature (10-wk) BMMC in vitro. Fluorescently labeled 2-wk c-kit ؉ BMMC, when injected intravenously, accumulated in response to intradermally injected PGE2. Analysis using TaqMan showed mRNA expression of the PGE2 receptors 3 (EP3) and 4 (EP4) on 2-and 10-wk BMMC. Chemotaxis induced by PGE2 was mimicked by EP3 agonists, blocked by an EP3 receptor antagonist, and partially inhibited by a MAPKK inhibitor. These results show an unexpected function for PGE2 in the chemotaxis of mast cells.allergy ͉ eicosanoids ͉ migration

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Suppression of allergic inflammation by the prostaglandin E receptor subtype EP3

Cited by 213 publications

References 41 publications

Prostaglandin E₂deficiency causes a phenotype of aspirin sensitivity that depends on platelets and cysteinyl leukotrienes

Prostaglandin E₂deficiency causes a phenotype of aspirin sensitivity that depends on platelets and cysteinyl leukotrienes

Prospective diagnostic analysis of copy number variants using SNP microarrays in individuals with autism spectrum disorders

Chemotactic action of prostaglandin E₂on mouse mast cells acting via the PGE₂receptor 3

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Suppression of allergic inflammation by the prostaglandin E receptor subtype EP3

Cited by 213 publications

References 41 publications

Prostaglandin E2deficiency causes a phenotype of aspirin sensitivity that depends on platelets and cysteinyl leukotrienes

Prostaglandin E2deficiency causes a phenotype of aspirin sensitivity that depends on platelets and cysteinyl leukotrienes

Prospective diagnostic analysis of copy number variants using SNP microarrays in individuals with autism spectrum disorders

Chemotactic action of prostaglandin E2on mouse mast cells acting via the PGE2receptor 3

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Prostaglandin E₂deficiency causes a phenotype of aspirin sensitivity that depends on platelets and cysteinyl leukotrienes

Prostaglandin E₂deficiency causes a phenotype of aspirin sensitivity that depends on platelets and cysteinyl leukotrienes

Chemotactic action of prostaglandin E₂on mouse mast cells acting via the PGE₂receptor 3