NON-COMPETITIVE, CHEMOKINE-MEDIATED INHIBITION OF BASIC FIBROBLAST GROWTH FACTOR-INDUCED ENDOTHELIAL CELL PROLIFERATION 
 
    Marco Presta1, Mirella Belleri1, Annunciata Vecchi2, Joseph Hesselgesser3, Alberto Mantovani1 and Richard Horuk3

1Unit of General Pathology and Immunology, Department of Biomedical Sciences and Biotechnology, University of Brescia, Brescia 25123, Italy; 2Istituto Ricerche Farmacologiche Mario Negri, 20157 Milan, Italy; 3Department of Immunology, Berlex Biosciences, Richmond CA 94804, USA
 
3D structure of IL-8 

 
 3D structure of IL-8 dimer 
 

If the plug-in named ChemScape Chime is properly installed on your computer, you should see a rotating 3D IL-8 molecule. The molecule can be moved by clicking it with the left button of your mouse and its characteristics, including automatic rotation, can be modified by clicking it with the right button.  

To download the plug-in: . 
 

 

Back to Presta's lab

 ABSTRACT 

The proinflammatory and chemoattractant chemokine interleukin-8 (IL-8) inhibits cell proliferation induced by basic fibroblast growth factor (bFGF) in mouse endothelial cells isolated from subcutaneous sponge implant (SIEC’s) and in bovine aortic endothelial GM 7373 cells. The mechanism of action of IL-8 was investigated in GM 7373 cells.  

IL-8 did not prevent the binding of bFGF to its tyrosine-kinase receptors (FGFRs) nor to cell-surface heparan sulfate proteoglycans (HSPGs). A transient interaction of IL-8 with the cell before the addition of the growth factor was sufficient to prevent bFGF activity. The inhibitory activity of IL-8 was abolished by protein kinase C (PKC) inhibitors and was mimicked by the PKC activator 12-O-tetradecanoyl phorbol 13-acetate (TPA). Accordingly, both IL-8 and TPA caused a ~60% decrease of the binding capacity of GM 7373 cells due to the down-regulation of FGFRs.  

Several C-X-C and C-C chemokines exerted an inhibitory action on bFGF activity similar to IL-8. Soluble heparin, 6-O-desulfated heparin, N-desulfated heparin, and heparan sulfate, but not 2-O-desulfated heparin, chondroitin-4-sulfate, hyaluronic acid, and K5 polysaccharide abrogated IL-8 inhibitory activity, consistently with the presence of low affinity, high capacity HSPG-like chemokine binding sites on GM 7373 cells. Finally, neovascularization induced by bFGF in murine subcutaneous sponge implants was reduced significantly by IL-8. 

In conclusion, IL-8 inhibits the mitogenic activity exerted by bFGF on cultured endothelial cells by a PKC-dependent, non-competitive mechanism of action that causes FGFR down-regulation. This activity is shared by several chemokines and requires endothelial cell surface HSPGs. The endothelial cell line utilized in the present study may help to elucidate the complex interplay among chemokines, HSPGs, growth factors and receptors in endothelial cells. 
 

J. Biol. Chem. (1998) 273:7911-7919. 

 
 
AIRC: Special Project Angiogenesis