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Published online before print January 10, 2007
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© by The Society for Leukocyte Biology
Journal of Leukocyte Biology, doi:10.1189/jlb.0906580

Received for publication September 20, 2006.
Revised November 14, 2006.
Accepted for publication December 11, 2006.

Article

Angiopoietin chemotactic activities on neutrophils are regulated by PI-3K activation

Alexandre Brkovic *, Martin Pelletier {dagger}, Denis Girard {dagger}, and Martin G. Sirois *@

*Research Center, Montreal Heart Institute, Department of Pharmacology, Université de Montréal, Montreal, Quebec, Canada; and {dagger}INRS-Institut Armand-Frappier, Pointe-Claire, Quebec, Canada

@ To whom correspondence should be addressed. E-mail: martin.sirois{at} icm-mhi.org.


  Abstract

Angiopoietins (Ang1 and Ang2) modulate blood vessel integrity during the angiogenic process through the activation of tyrosine kinase receptor (Tie2). We recently detected Tie2 expression on neutrophils and reported that angiopoietins induce acute proinflammatory events including neutrophil {beta}2-integrin activation and their adhesion onto endothelial cells. Herein, we investigated the effect of angiopoietins on neutrophil migration and their capacity to modulate CXCL8/IL-8 chemotactic properties. Using a Boyden chamber assay, we observed that Ang1 and Ang2 (up to 10 nM; 60 min) increased the migration of neutrophils, and the maximal effect was achieved at 1 nM (72% and 114% increase, respectively) as compared with untreated cells. Angiopoietins induce a rapid and transient Akt phosphorylation, and pretreatment of neutrophils with PI-3K inhibitors, wortmannin (100 nM) and LY294002 (500 nM), reduced Ang1-mediated neutrophil migration by 100% and 78% and Ang2 chemotactic activity by 100% and 71%, respectively. Treatment of neutrophils with CXCL8/IL-8 (up to 50 nM; 60 min) increased basal neutrophil migration by 257% at its optimal concentration (10 nM), and pretreatment of neutrophils with corresponding PI-3K inhibitors reduced the CXCL8/IL-8 (1 nM) chemotactic effect. Pretreatment of neutrophils with Ang1 or Ang2 (10 nM; 15 min) potentiated neutrophil migration induced by CXCL8/IL-8 (1 or 10 nM; 60 min) by 263% and 238% and by 177% and 164%, respectively. Finally, both angiopoietins showed a synergistic effect on the induction of Akt phosphorylation mediated by CXCL8/IL-8. In summary, our data demonstrate that angiopoietins increase neutrophil migration through PI-3K activation and can enhance proinflammatory activities of other cytokines.

Key Words: cytokines • polymorphonuclear cells • migration • Tie2 receptor




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R. Maliba, A. Brkovic, P.-E. Neagoe, L. R. Villeneuve, and M. G. Sirois
Angiopoietin-mediated endothelial P-selectin translocation: cell signaling mechanisms
J. Leukoc. Biol., February 1, 2008; 83(2): 352 - 360.
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