11-Dehydro-thromboxane B2, a Stable Thromboxane Metabolite, Is a Full Agonist of Chemoattractant Receptor-homologous Molecule Expressed on TH2 Cells (CRTH2) in Human Eosinophils and Basophils

Böhm, Eva; Sturm, Eva; Weiglhofer, Iris; Sandig, Hilary; Shichijo, Michitaka; McNamee, Anne; Pease, James E.; Kollroser, Manfred; Peskar, Bernhard A.; Heinemann, Ákos

doi:10.1074/jbc.m310270200

Cited by 97 publications

(68 citation statements)

References 49 publications

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“…While the human, mouse, and rat 11-TXDH isoforms have not been identified, 11dh-TXB 2 has been detected in urine samples from these species. Historically, TXB 2 and 11dh-TXB 2 have been considered biologically inert due to their inability to activate the thromboxane TP receptor (226), but work by Böhm et al (227) demonstrates that 11dh-TXB 2 is an agonist of the CRTH2 receptor.…”

Section: -Hydroxythromboxane B 2 Reductasementioning

confidence: 99%

Thematic Review Series: Proteomics. An integrated omics analysis of eicosanoid biology

Buczynski

Dumlao

Dennis

2009

Journal of Lipid Research

475

463

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Eicosanoids have been implicated in a vast number of devastating inflammatory conditions, including arthritis, atherosclerosis, pain, and cancer. Currently, over a hundred different eicosanoids have been identified, with many having potent bioactive signaling capacity. These lipid metabolites are synthesized de novo by at least 50 unique enzymes, many of which have been cloned and characterized. Due to the extensive characterization of eicosanoid biosynthetic pathways, this field provides a unique framework for integrating genomics, proteomics, and metabolomics toward the investigation of disease pathology. To facilitate a concerted systems biology approach, this review outlines the proteins implicated in eicosanoid biosynthesis and signaling in human, mouse, and rat. Applications of the extensive genomic and lipidomic research to date illustrate the questions in eicosanoid signaling that could be uniquely addressed by a thorough analysis of the entire eicosanoid proteome.-Buczynski, M. W., D. S. Dumlao, and E. A. Dennis. An integrated omics analysis of eicosanoid biology.

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Section: -Hydroxythromboxane B 2 Reductasementioning

confidence: 99%

Thematic Review Series: Proteomics. An integrated omics analysis of eicosanoid biology

Buczynski

Dumlao

Dennis

2009

Journal of Lipid Research

475

463

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“…In addition, CRTH2 is activated by several PGD 2 metabolites, including 13,14-dihydro-15-keto-(DK)-PGD 2 , PGJ 2 , ⌬ 12 PGJ 2 , and 15-deoxy-PGJ 2 (7,8) and a thromboxane (TX) metabolite, 11-dehydro-TXB 2 (9). Moreover, CRTH2 mediates the respiratory burst and degranulation of eosinophils (8,10), induces the production of proinflammatory cytokines in Th2 cells (11), and enhances the release of histamine from basophils (12).…”

Section: P Rostaglandin (Pg)mentioning

confidence: 99%

The Role of the Prostaglandin D2 Receptor, DP, in Eosinophil Trafficking

Schratl¹,

Royer²,

Kostenis³

et al. 2007

The Journal of Immunology

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Prostaglandin (PG) D2 is a major mast cell product that acts via two receptors, the D-type prostanoid (DP) and the chemoattractant receptor-homologous molecule expressed on Th2 cells (CRTH2) receptors. Whereas CRTH2 mediates the chemotaxis of eosinophils, basophils, and Th2 lymphocytes, the role of DP has remained unclear. We report in this study that, in addition to CRTH2, the DP receptor plays an important role in eosinophil trafficking. First, we investigated the release of eosinophils from bone marrow using the in situ perfused guinea pig hind limb preparation. PGD2 induced the rapid release of eosinophils from bone marrow and this effect was inhibited by either the DP receptor antagonist BWA868c or the CRTH2 receptor antagonist ramatroban. In contrast, BWA868c did not inhibit the release of bone marrow eosinophils when this was induced by the CRTH2-selective agonist 13,14-dihydro-15-keto-PGD2. In additional experiments, we isolated bone marrow eosinophils from the femoral cavity and found that these cells migrated toward PGD2. We also observed that BWA868c inhibited this response to a similar extent as ramatroban. Finally, using immunohistochemistry we could demonstrate that eosinophils in human bone marrow specimens expressed DP and CRTH2 receptors at similar levels. Eosinophils isolated from human peripheral blood likewise expressed DP receptor protein but at lower levels than CRTH2. In agreement with this, the chemotaxis of human peripheral blood eosinophils was inhibited both by BWA868c and ramatroban. These findings suggest that DP receptors comediate with CRTH2 the mobilization of eosinophils from bone marrow and their chemotaxis, which might provide the rationale for DP antagonists in the treatment of allergic disease.

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“…Blood samples were obtained from healthy volunteers according to a protocol approved by the Ethics Committee of the University of Graz and were processed as described previously (Bohm et al, 2004). Preparations of polymorphonuclear leukocytes (containing eosinophils and neutrophils) were prepared by dextran sedimentation of citrated whole blood and Histopaque gradients.…”

Section: Functional Selectivity Of Crth2 Ligandsmentioning

confidence: 99%

“…It induces intracellular calcium mobilization and chemotaxis in Th2 cells in a G␣i-dependent manner (Hirai et al, 2001). CRTH2 has also been shown to mediate PGD2-induced shape change of eosinophils, an effect that could be attenuated with the phospholipase C␤ inhibitor U73122 (Bohm et al, 2004). Functional experiments performed in HEK293 cells stably expressing CRTH2 have shown that it negatively regulates adenylyl cyclase via G␣i/o proteins (Sawyer et al, 2002).…”

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confidence: 99%

Identification of Indole Derivatives Exclusively Interfering with a G Protein-Independent Signaling Pathway of the Prostaglandin D2 Receptor CRTH2

Mathiesen¹,

Ulven²,

Martini³

et al. 2005

Mol Pharmacol

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The anti-inflammatory drugs indomethacin and ramatroban, the latter showing clinical efficacy in treating allergic asthma, have been shown to act as a classic agonist and antagonist, respectively, of the G protein-coupled chemoattractant receptorhomologous molecule expressed on Th2 cells (CRTH2 receptor). Here, we report the identification of two indole derivatives 1-(4-ethoxyphenyl)-5-methoxy-2-methylindole-3-carboxylic acid and N ␣ -tosyltryptophan (hereafter referred to as 1 and 2, respectively), which are structurally related to indomethacin and ramatroban but which selectively interfere with a specific G protein-independent signaling pathway of CRTH2. In whole-cell saturation-binding assays, 1 and 2 both increase the number of [ 3 H]prostaglandin D2 (PGD2)-recognizing CRTH2 sites and the affinity of PGD2 for CRTH2. Enzyme-linked immunosorbent assays show that they do not alter the total number of CRTH2 receptors on the cell surface. Analysis of their binding mode indicates that unlike indomethacin or ramatroban, 1 and 2 can occupy CRTH2 simultaneously with PGD2. On a functional level, however, 1 and 2 do not interfere with PGD2-mediated activation of heterotrimeric G proteins by CRTH2. In contrast, both compounds inhibit PGD2-mediated arrestin translocation via a G protein-independent mechanism. In human eosinophils endogenously expressing CRTH2, 1 selectively decreases the efficacy but not the potency of PGD2-induced shape change, unlike ramatroban, which displays competitive antagonistic behavior. These data show for the first time that "antagonists" can cause markedly dissimilar degrees of inhibition for different effector pathways and suggest that it may be possible to develop novel classes of specific signal-inhibiting drugs distinct from conventional antagonists.The proximal event mediating cellular signaling by a seven-transmembrane (7TM) receptor is the binding of ligand, which causes the receptor to change its behavior toward the cell. In the past, ligands targeting 7TM receptors have been believed to cause a single type of functional response for all effectors linked to a given receptor; thus, compounds were classified as agonists or antagonists/inverse agonists, respectively, according to their intrinsic efficacy. Drugs with positive intrinsic efficacy stabilize the active receptor conformation and elicit a signaling response (agonists), whereas drugs with negative intrinsic efficacy preferentially stabilize the inactive receptor conformation and shut down a signaling response (antagonists/inverse agonists). In addition, this traditional view of either turning on or off receptor responses has been linked exclusively to signaling pathways involving the activation of heterotrimeric G pro- Article, publication date, and citation information can be found at http://molpharm.aspetjournals.org. doi:10.1124/mol.104.010520.ABBREVIATIONS: 7TM, seven transmembrane; CRTH2, chemoattractant receptor-homologous molecule expressed on Th2 cells; PGD2, prostaglandin D2; ELISA, enzyme-linked immunosorbent a...

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11-Dehydro-thromboxane B2, a Stable Thromboxane Metabolite, Is a Full Agonist of Chemoattractant Receptor-homologous Molecule Expressed on TH2 Cells (CRTH2) in Human Eosinophils and Basophils

Cited by 97 publications

References 49 publications

Thematic Review Series: Proteomics. An integrated omics analysis of eicosanoid biology

Thematic Review Series: Proteomics. An integrated omics analysis of eicosanoid biology

The Role of the Prostaglandin D2 Receptor, DP, in Eosinophil Trafficking

Identification of Indole Derivatives Exclusively Interfering with a G Protein-Independent Signaling Pathway of the Prostaglandin D2 Receptor CRTH2

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