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

Daniel Martin,J.Silvio Gutkind,Rebeca Galisteo

doi:10.1074/jbc.c800207200

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 (HIF1alpha), which becomes active in hypoxic tissues, leading to the synthesis and secretion of VEGF. The role of HIF1alpha 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 HIF1alpha but instead requires the activation of the transcription factor NFkappaB. Furthermore, we identified the components of the CBM complex, Carma3, Bcl10, and Malt1, as key mediators of the CXCL8/IL8-induced NFkappaB activation and VEGF up-regulation. Together, these findings support the existence of an NFkappaB-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.

Highlights

The members of the vascular endothelial growth factor (VEGF)[2] family of proteins are members of the platelet-derived growth factor superfamily of polypeptide growth factors, which bind and activate their cognate tyrosine kinase receptors, VEGF receptors 1, 2, and 3 (VEGFR1, VEGFR2, and VEGFR3), thereby promoting the proliferation, survival, and migration of endothelial cells (1)
The production and secretion of VEGF is regulated by a well understood mechanism by which cells deprived of oxygen induce the expression of this potent angiogenic factor through the activation of the hypoxia-inducible factor-1 (HIF1), which in turn increases the formation of blood vessels and restores the supply of nutrients and oxygen (4)
The HIF1 transcription factor is composed of two subunits, HIF1␣ and HIF1␤, the former being synthesized in most cells but rapidly degraded by a mechanism that involves its oxygen-dependent ubiquitination and degradation in the proteasome (4)

Summary

Introduction

The members of the vascular endothelial growth factor (VEGF)[2] family of proteins are members of the platelet-derived growth factor superfamily of polypeptide growth factors, which bind and activate their cognate tyrosine kinase receptors, VEGF receptors 1, 2, and 3 (VEGFR1, VEGFR2, and VEGFR3), thereby promoting the proliferation, survival, and migration of endothelial cells (1). We show here that CXCL8/IL8 promotes the NF␬B-dependent autocrine activation of VEGFR2 receptors in endothelial cells by modulating their intracellular VEGF pool, which in turn may contribute to the proangiogenic response to inflammatory processes.

Results

Conclusion