HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

J. Biol. Chem., Vol. 279, Issue 9, 7663-7670, February 27, 2004

This Article Full Text Full Text (PDF) All Versions of this Article: 279/9/7663    most recent M310270200v1 Submit a Letter to Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Böhm, E. Articles by Heinemann, A. Search for Related Content PubMed PubMed Citation Articles by Böhm, E. Articles by Heinemann, A. Social Bookmarking                      What's this?

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^*

Eva Böhm, Gunter J. Sturm, Iris Weiglhofer, Hilary Sandig, Michitaka Shichijo¶, Anne McNamee||, James E. Pease, Manfred Kollroser**, Bernhard A. Peskar, and Akos Heinemann

From the Departments of Experimental and Clinical Pharmacology and ^**Forensic Medicine, Medical University Graz, A-8010 Graz, Austria, Leukocyte Biology Section, Biomedical Sciences Division, Imperial College Faculty of Medicine, Imperial College of Science, Technology and Medicine, South Kensington, London SW7 2AZ, United Kingdom, ^¶Respiratory Research, Research Center Kyoto, Bayer Yakuhin Ltd., Kizu-cho Soraku-gun, Kyoto 619-0216, Japan, and ^||Immunopharmacology Department, GlaxoSmithKline Place, Stevenage SG1 2NY, United Kingdom

Thromboxane (TX) A₂, a cyclooxygenase-derived mediator involved in allergic responses, is rapidly converted in vivo to a stable metabolite, 11-dehydro-TXB₂, which is considered to be biologically inactive. In this study, we found that 11-dehydro-TXB₂, but not the TXA₂ analogue U46,619 or TXB₂, activated eosinophils and basophils, as assayed by flow cytometric shape change. 11-Dehydro-TXB₂ was also chemotactic for eosinophils but did not induce, nor inhibit, platelet aggregation. Chemoattractant receptor-homologous molecule expressed on TH2 cells (CRTH2) is an important chemoattractant receptor expressed by eosinophils, basophils, and TH2 lymphocytes, and prostaglandin (PG)D₂ has been shown to be its principal ligand. 11-Dehydro-TXB₂ induced calcium flux mainly from intracellular stores in eosinophils, and this response was desensitized after stimulation with PGD₂ but not other eosinophil chemoattractants. Shape change responses of eosinophils and basophils to 11-dehydro-TXB₂ were inhibited by the thromboxane (TP)/CRTH2 receptor antagonist ramatroban, but not the selective TP antagonist SQ29,548, and were insensitive to pertussis toxin. The phospholipase C inhibitor U73,122 attenuated both 11-dehydro-TXB₂- and PGD₂-induced shape change. 11-Dehydro-TXB₂ also induced the chemotaxis of BaF/3 cells transfected with hCRTH2 but not naive BaF/3 cells. At a threshold concentration, 11-dehydro-TXB₂ had no antagonistic effect on CRTH2-mediated responses as induced by PGD2. These data show that 11-dehydro-TXB₂ is a full agonist of the CRTH2 receptor and hence might cause CRTH2 activation in cellular contexts where PGD-synthase is not present. Given its production in the allergic lung, antagonism of the 11-dehydro-TXB₂/CRTH2axis may be of therapeutic relevance.

Received for publication, September 16, 2003 , and in revised form, December 9, 2003.

^* This work was supported by the Royal Society, the Austrian Academy of Sciences, Jubiläumsfonds of the Austrian National Bank Grant 10005 (to A. H.), Austrian Science Fund Grant P15453 (to A. H.), GlaxoSmithKline/Biotechnology and Biological Sciences Research Council Case Studentship (to H. S.), and Wellcome Trust Programme Grant 038775/Z/96/A (to J. E. P.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence should be addressed: Dept. of Experimental and Clinical Pharmacology, Medical University Graz, Universitaetsplatz 4, A-8010 Graz, Austria. Tel.: 43-316-380-4508; Fax: 43-316-380-9645; E-mail: akos.heinemann{at}uni-graz.at.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

				M. W. Buczynski, D. S. Dumlao, and E. A. Dennis Thematic Review Series: Proteomics. An integrated omics analysis of eicosanoid biology J. Lipid Res., June 1, 2009; 50(6): 1015 - 1038. [Abstract] [Full Text] [PDF]

				R. Schroder, N. Merten, J. M. Mathiesen, L. Martini, A. Kruljac-Letunic, F. Krop, A. Blaukat, Y. Fang, E. Tran, T. Ulven, et al. The C-terminal Tail of CRTH2 Is a Key Molecular Determinant That Constrains G{alpha}i and Downstream Signaling Cascade Activation J. Biol. Chem., January 9, 2009; 284(2): 1324 - 1336. [Abstract] [Full Text] [PDF]

				R. Schuligoi, M. Sedej, M. Waldhoer, A. Vukoja, E. M. Sturm, I. T. Lippe, B. A. Peskar, and A. Heinemann Prostaglandin H2 induces the migration of human eosinophils through the chemoattractant receptor homologous molecule of Th2 cells, CRTH2 J. Leukoc. Biol., January 1, 2009; 85(1): 136 - 145. [Abstract] [Full Text] [PDF]

				P. Schratl, J. F. Royer, E. Kostenis, T. Ulven, E. M. Sturm, M. Waldhoer, G. Hoefler, R. Schuligoi, I. Th. Lippe, B. A. Peskar, et al. The Role of the Prostaglandin D2 Receptor, DP, in Eosinophil Trafficking J. Immunol., October 1, 2007; 179(7): 4792 - 4799. [Abstract] [Full Text] [PDF]

				J. M. Mathiesen, A. Christopoulos, T. Ulven, J. F. Royer, M. Campillo, A. Heinemann, L. Pardo, and E. Kostenis On the Mechanism of Interaction of Potent Surmountable and Insurmountable Antagonists with the Prostaglandin D2 Receptor CRTH2 Mol. Pharmacol., April 1, 2006; 69(4): 1441 - 1453. [Abstract] [Full Text] [PDF]

				J. M. Mathiesen, T. Ulven, L. Martini, L. O. Gerlach, A. Heinemann, and E. Kostenis Identification of Indole Derivatives Exclusively Interfering with a G Protein-Independent Signaling Pathway of the Prostaglandin D2 Receptor CRTH2 Mol. Pharmacol., August 1, 2005; 68(2): 393 - 402. [Abstract] [Full Text] [PDF]

				G. Monneret, R. Boumiza, S. Gravel, C. Cossette, J. Bienvenu, J. Rokach, and W. S. Powell Effects of Prostaglandin D2 and 5-Lipoxygenase Products on the Expression of CD203c and CD11b by Basophils J. Pharmacol. Exp. Ther., February 1, 2005; 312(2): 627 - 634. [Abstract] [Full Text] [PDF]