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Prepublished online as a Blood First Edition Paper on April 10, 2003; DOI 10.1182/blood-2002-09-2773. This Article Full Text (PDF) All Versions of this Article: 2002-09-2773v1 102/3/789    most recent Alert me when this article is cited Alert me if a correction is posted 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 Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Ogilvie, P. Articles by Uguccioni, M. Search for Related Content PubMed PubMed Citation Articles by Ogilvie, P. Articles by Uguccioni, M. Social Bookmarking                   What's this? Submitted September 11, 2002 Accepted March 11, 2003 Eotaxin-3 is a natural antagonist for CCR2 and exerts a repulsive effect on human monocytes Patricia Ogilvie, Samantha Paoletti, Ian Clark-Lewis, and Mariagrazia Uguccioni* Institute for Research in Biomedicine, Bellinzona, Switzerland Biochemical Research Center, University of British Columbia, Vancouver, Canada * Corresponding author; email: mariagrazia.uguccioni{at}irb.unisi.ch. Eotaxin-3 (CCL26) belongs to the group of CC chemokines that attract eosinophils, basophils, and Th2 lymphocytes. Like eotaxin (CCL11) and eotaxin-2 (CCL24), eotaxin-3 mediates its activity through CCR3. Here we show that eotaxin-3 also binds to CCR2 on monocytes and CCR2-transfected cells. In contrast to MCP-1 (CCL2), eotaxin-3 does not trigger intracellular calcium mobilization, enzyme release, or phosphorylation of the MAP kinase ERK, and induces a weak chemotaxis in monocytes. Instead, eotaxin-3 inhibits MCP-1-mediated responses, thus acting as a natural antagonist for CCR2. This study also demonstrates that eotaxin-3 promotes active movement of monocytes away from a gradient of eotaxin-3 in vitro. This repellent effect is amplified when an additional gradient of MCP-1 is applied, demonstrating that the two mechanisms are synergistic. Eotaxin-3 effects on monocytes are largely abolished when cells are pretreated with MCP-1, or CCR2 antagonists. Like MCP-1-mediated migration, repulsion is Bordetella pertussis toxin sensitive, indicating the involvement of Gi protein-coupled receptors. However, using singly receptor-transfected cells expressing CCR2 we could not detect F-actin formation or an active movement away induced by eotaxin-3, suggesting that either expression of a single receptor type is not sufficient to mediate cell repulsion or that the used transfected cell lines lack additional interaction molecules that are required for reverse migration. Eotaxin-3 was shown to be expressed by vascular endothelial cells and to be essential for endothelial transmigration of eosinophils. Our data provide a mechanism by which two chemokine gradients that are oriented in opposite directions could cooperate in efficiently driving out monocytes from blood vessels into tissue. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: J. Y. Lee, C. D. Buzney, M. C. Poznansky, and R. Sackstein Dynamic alterations in chemokine gradients induce transendothelial shuttling of human T cells under physiologic shear conditions J. Leukoc. Biol., December 1, 2009; 86(6): 1285 - 1294. [Abstract] [Full Text] [PDF] C. Lange, D. J. Starrett, J. Goetsch, V. Gerke, and U. Rescher Transcriptional profiling of human monocytes reveals complex changes in the expression pattern of inflammation-related genes in response to the annexin A1-derived peptide Ac1-25 J. Leukoc. 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