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Titre du document / Document title

CXCL8/IL8 Stimulates Vascular Endothelial Growth Factor (VEGF) Expression and the Autocrine Activation of VEGFR2 in Endothelial Cells by Activating NFKB through the CBM (Carma3/Bcl10/Malt1) Complex

Auteur(s) / Author(s)

MARTIN Daniel ; GALISTEO Rebeca ; SILVIO GUTKIND J. ;

Résumé / Abstract

Vascular endothelial growth factor (VEGF) is a potent mitogen and permeability factor for endothelial cells that plays a central role in angiogenesis, vascular maintenance, inflammation, and cancer. VEGF also mediates the homeostatic adaptation to hypoxic conditions by promoting an increase in vascular density to compensate for decreased oxygenation. This process is triggered by an oxygen-sensitive transcription factor, hypoxia-inducible factor-1 (HIFIa), which becomes active in hypoxic tissues, leading to the synthesis and secretion of VEGF. The role of HIFIa in other processes that involve angiogenesis such as in inflammation is less clear. Of interest, endothelial cells not only respond to but also store and secrete VEGF, which is required for the maintenance of the integrity of the vascular system. How this intracellular pool of VEGF is regulated is still not understood. Here, we found that CXCL8/IL8, a potent proangiogenic and inflammatory chemokine, up-regulates VEGF mRNA and protein levels in endothelial cells by acting on its cognate receptor, CXCR2, and that this results in the autocrine activation of VEGFR2. Surprisingly, this process does not involve HIF1α but instead requires the activation of the transcription factor NFKB. Furthermore, we identified the components of the CBM complex, Carma3, Bcl10, and Maltl, as key mediators of the CXCL8/IL8-induced NFκB activation and VEGF up-regulation. Together, these findings support the existence of an NFκB-mediated pathway by which the proinflammatory chemokine CXCL8/IL8 controls the expression of VEGF in endothelial cells, thereby promoting the activation of VEGF receptors in an autocrine fashion.

Revue / Journal Title

The Journal of biological chemistry    ISSN  0021-9258   CODEN JBCHA3 

Source / Source

2009, vol. 284, no10, pp. 6038-6042 [5 page(s) (article)]

Langue / Language

Anglais

Editeur / Publisher

American Society for Biochemistry and Molecular Biology, Bethesda, MD, ETATS-UNIS  (1905) (Revue)

Localisation / Location

INIST-CNRS, Cote INIST : 3082, 35400018554551.0040

Nº notice refdoc (ud4) : 21224027



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