Inhibition of lipopolysaccharide and IL-1 but not of TNF-induced activation of human endothelial cells by suramin.
The binding and trans-endothelium migration of inflammatory cells is believed to play a critical role in a variety of inflammatory conditions. This study investigates the ability of the experimental drug suramin to block the activation of HUVEC by endotoxin and by the proinflammatory cytokines IL-1 and TNF. We demonstrate that the inducible expression of several adhesion molecules by LPS and IL-1 beta but not by TNF-alpha is prevented by suramin. In a dose-dependent manner, suramin inhibits the binding of neutrophils and T lymphocytes to LPS and IL-1 beta but not to TNF-alpha-activated HUVEC. The inhibitory effect of the drug on IL-1 beta-induced but not on LPS-induced cell stimulation can be completely reversed by the addition of excess cytokine but not by excess LPS. Because LPS activation of HUVEC is known to depend on serum/plasma-derived soluble CD14, we set out to determine whether suramin inhibition involves interference with the action of the CD14-LPS complex on HUVEC. Indeed, the drug prevents the binding of radioactive LPS in the presence of serum and inhibits LPS-induced cell activation in serum-free medium supplemented with recombinant soluble CD14. The results suggest that suramin interferes with the CD14-dependent activation of HUVEC and that it also may be a useful agent in blocking infectious endotheliopathies in vivo.
Strassmann
G
G
Department of Immunology, Otsuka America Pharmaceutical Inc., Rockville, MD 20850.
Graber
N
N
Goyert
S M
SM
Fong
M
M
McCullers
S
S
Rong
G W
GW
Beall
L D
LD
D002448:Cell Adhesion / Q000187:drug effects; D015815:Cell Adhesion Molecules / Q000378:metabolism; D019040:E-Selectin; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects*; D006801:Humans; D066298:In Vitro Techniques; D018799:Intercellular Adhesion Molecule-1; D007375:Interleukin-1 / Q000037:antagonists & inhibitors*; D008070:Lipopolysaccharides / Q000037:antagonists & inhibitors*; D009504:Neutrophils / Q000166:cytology; D013498:Suramin / Q000494:pharmacology*; D013601:T-Lymphocytes / Q000166:cytology; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors*; D019010:Vascular Cell Adhesion Molecule-1
D015815:Cell Adhesion Molecules; D019040:E-Selectin; D007375:Interleukin-1; D008070:Lipopolysaccharides; D014409:Tumor Necrosis Factor-alpha; D019010:Vascular Cell Adhesion Molecule-1; D018799:Intercellular Adhesion Molecule-1; D013498:Suramin