Initial attachment of leukocytes to the vessel wall at sites of inflammation is supported by a family of carbohydrate-binding adhesion molecules called the selectins. Selectin ligands include sialyl-Lewis x (sLe(x), Neu5Acα2-3Galβ1-4[Fucα1-3]GlcNAc-) and related structures. We report here that defined heparin oligosaccharides interact with the selectins. Heparin chains containing four or more monosaccharide residues inhibited the function of L- and P-selectin, but not E-selectin, in vitro. In a competition enzyme-linked immunosorbent assay measuring inhibition of solution-phase selectin-Ig fusion proteins (selectin-Ig) binding to immobilized bovine serum albumin-sLe(x) neoglycoprotein, a heparin-derived tetrasaccharide mixture inhibited 50% of L- and P-selectin-Ig binding (IC50) at 200 ± 40 μmol/L and 850 ± 110 μmol/L, respectively. A single hexasulfated tetrasaccharide (ΔUA2Sα1-4GlcNS6Sα1-4IdoA2Sα1-4GlcNS6S) was particularly active against L- and P-selectin-Ig (IC50 = 46 ± 5 μmol/L and 341 ± 24 μmol/L). By comparison, the tetrasaccharide sLe(x) was not inhibitory at concentrations up to 1 mmol/L. In cell adhesion assays, heparin tetrasaccharides reduced binding of neutrophils to COS cells expressing P- selectin but not to COS cells expressing E-selectin. They also blocked colon cancer cell adhesion to L- and P-selectin but not E-selectin. In a model of acute inflammation, intravenously administered heparin tetrasaccharides diminished influx of neutrophils into the peritoneal cavities of thioglycollate-treated mice. We conclude that heparin oligosaccharides, including non-anticoagulant tetrasaccharides, are effective L- and P-selectin inhibitors in vitro and have anti-inflammatory activity in vivo.
CITATION STYLE
Nelson, R. M., Cecconi, O., Roberts, W. G., Aruffo, A., Linhardt, R. J., & Bevilacqua, M. P. (1993). Heparin oligosaccharides bind L- and P-selectin and inhibit acute inflammation. Blood, 82(11), 3253–3258. https://doi.org/10.1182/blood.v82.11.3253.3253
Mendeley helps you to discover research relevant for your work.