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Blood, 15 April 2008, Vol. 111, No. 8, pp. 4145-4154.
Prepublished online as a Blood First Edition Paper on February 5, 2008; DOI 10.1182/blood-2007-08-110338.
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Submitted August 30, 2007
Accepted January 30, 2008
Angiopoietin-1 promotes endothelial cell proliferation and migration through AP-1-dependent autocrine production of interleukin-8
Nelly A. Abdel-Malak, Coimbatore B. Srikant, Arnold S Kristof, Sheldon A Magder, John A Di Battista, and Sabah N.A. Hussain*
Critical Care and Respiratory Divisions and Meakins-Christie Laboratories, Department of Medicine, McGill University Health Centre, McGill University, Montreal, Quebec, Canada
Division of Endocrinology, Department of Medicine, McGill University Health Centre, McGill University, Montreal, Quebec, Canada
Division of Rehumatology, Department of Medicine, McGill University Health Centre, McGill University, Montreal, Quebec, Canada
* Corresponding author; email: sabah.hussain{at}muhc.mcgill.ca.
Angiopoietin-1 (Ang-1), ligand for the endothelial cell-specific Tie-2 receptors, promotes migration and proliferation of endothelial cells, however, whether these effects are promoted through the release of a secondary mediator remains unclear. In this study, we assessed whether Ang-1 promotes endothelial cell migration and proliferation through the release of interleukin-8 (IL-8). Ang-1 elicited in human umbilical vein endothelial cells (HUVECs) a dose-and time-dependent increase in IL-8 production as a result of induction of mRNA and enhanced mRNA stability of IL-8 transcripts. IL-8 production is also elevated in HUVECs transduced with retroviruses expressing Ang-1. Neutralization of IL-8 in these cells with a specific antibody significantly attenuated proliferation and migration and induced caspase-3 activation. Exposure to Ang-1 triggered a significant increase in DNA binding of activator protein-1 (AP-1) to a relatively short fragment of IL-8 promoter. Upstream from the AP-1 complex, upregulation of IL-8 transcription by Ang-1 was mediated through the Erk1/2, SAPK/JNK and PI-3 kinase pathways which triggered c-Jun phosphorylation on Ser63 and Ser73. These results suggest that promotion of endothelial migration and proliferation by Ang-1 is mediated, in part, through the production of IL-8, which acts in an autocrine fashion to suppress apoptosis and facilitate cell proliferation and migration.
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