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 (sponge- induced mouse endothelial cells) 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 FGF receptors (FGFRs) nor to cell surface heparan sulfate proteoglycans (HSPGs). A transient interaction of ILl-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-tetradecanoylphorbol-13-acetate. Accordingly, both IL-8 and 12-O-tetradecanoylphorbol-13-acetate 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, noncompetitive 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.
| Original language | English |
|---|---|
| Pages (from-to) | 7911-7919 |
| Number of pages | 9 |
| Journal | Journal of Biological Chemistry |
| Volume | 273 |
| Issue number | 14 |
| DOIs | |
| Publication status | Published - Apr 3 1998 |
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ASJC Scopus subject areas
- Biochemistry
Cite this
Noncompetitive, chemokine-mediated inhibition of basic fibroblast growth factor-induced endothelial cell proliferation. / Presta, Marco; Belleri, Mirella; Vecchi, Annunciata; Hesselgesser, Joseph; Mantovani, Alberto; Horuk, Richard.
In: Journal of Biological Chemistry, Vol. 273, No. 14, 03.04.1998, p. 7911-7919.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Noncompetitive, chemokine-mediated inhibition of basic fibroblast growth factor-induced endothelial cell proliferation
AU - Presta, Marco
AU - Belleri, Mirella
AU - Vecchi, Annunciata
AU - Hesselgesser, Joseph
AU - Mantovani, Alberto
AU - Horuk, Richard
PY - 1998/4/3
Y1 - 1998/4/3
N2 - 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 (sponge- induced mouse endothelial cells) 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 FGF receptors (FGFRs) nor to cell surface heparan sulfate proteoglycans (HSPGs). A transient interaction of ILl-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-tetradecanoylphorbol-13-acetate. Accordingly, both IL-8 and 12-O-tetradecanoylphorbol-13-acetate 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, noncompetitive 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.
AB - 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 (sponge- induced mouse endothelial cells) 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 FGF receptors (FGFRs) nor to cell surface heparan sulfate proteoglycans (HSPGs). A transient interaction of ILl-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-tetradecanoylphorbol-13-acetate. Accordingly, both IL-8 and 12-O-tetradecanoylphorbol-13-acetate 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, noncompetitive 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.
UR - http://www.scopus.com/inward/record.url?scp=0032478616&partnerID=8YFLogxK
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U2 - 10.1074/jbc.273.14.7911
DO - 10.1074/jbc.273.14.7911
M3 - Article
C2 - 9525887
AN - SCOPUS:0032478616
VL - 273
SP - 7911
EP - 7919
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
SN - 0021-9258
IS - 14
ER -