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Blood, 15 July 2005, Vol. 106, No. 2, pp. 436-443. Prepublished online as a Blood First Edition Paper on March 31, 2005; DOI 10.1182/blood-2005-02-0489. This Article Full Text (PDF) All Versions of this Article: 2005-02-0489v1 106/2/436    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 Fulkerson, P. C Articles by Rothenberg, M. E Search for Related Content PubMed PubMed Citation Articles by Fulkerson, P. C Articles by Rothenberg, M. E Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted February 7, 2005 Accepted March 23, 2005 CXCL9 inhibits eosinophil responses by a CCR3- and Rac2-dependent mechanism Patricia C Fulkerson, Hongyan Zhu, Nives Zimmermann, and Marc E Rothenberg* Department of Molecular Genetics, Biochemistry and Microbiology, University of Cincinnati College of Medicine, Cincinnati, OH, USA Department of Molecular and Developmental Biology, University of Cincinnati College of Medicine, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA Division of Allergy and Immunology, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, OH, USA * Corresponding author; email: Marc.Rothenberg{at}cchmc.org. Recently, inhibitory cytokine pathways for leukocyte chemoattraction and activation have been identified, but there is little insight into the operational mechanisms except for models that rely on simple receptor antagonism. We have previously identified the existence of a murine eosinophil inhibitory pathway mediated by the chemokine CXCL9 (Mig) that impressively blocks eosinophil chemoattraction and function, but the mechanism has remained elusive. We now demonstrate that Mig's inhibitory action extends beyond receptor antagonism alone. Notably, in addition to inhibiting eotaxin-induced F-actin formation and chemoattraction, Mig potently blocks PAF- and LTB4-induced responses. Remarkably, Mig-treated eosinophils display an abnormal F-actin assembly in the absence of agonist stimulation. Additionally, Mig pre-treatment inhibits eotaxin-induced activation of the Rho-GTPase Rac and Rac2-deficient eosinophils demonstrate an impaired transmigration and actin polymerization response to eotaxin stimulation. Furthermore, Mig was unable to inhibit eotaxin-induced responses in Rac2-deficient eosinophils. Finally, using CCR3 gene-targeted cells, Mig's inhibitory activity is demonstrated to be mediated by CCR3. Thus, by altering agonist-induced signaling and abrogating cytoskeletal reorganization by a Rac2-dependent mechanism, Mig markedly inhibits eosinophil responses to diverse stimuli. These results establish evidence that distinct chemokines can utilize CCR3 to induce opposing signals in eosinophils. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: A. Munitz, I. Bachelet, R. Eliashar, A. Moretta, L. Moretta, and F. Levi-Schaffer The inhibitory receptor IRp60 (CD300a) suppresses the effects of IL-5, GM-CSF, and eotaxin on human peripheral blood eosinophils Blood, March 1, 2006; 107(5): 1996 - 2003. [Abstract] [Full Text] [PDF]

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