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Heparin oligosaccharides bind L- and P-selectin and inhibit acute
inflammation
RM Nelson, O Cecconi, WG Roberts, A Aruffo, RJ Linhardt and MP Bevilacqua
Howard Hughes Medical Institute, University of California, San Diego, La
Jolla.
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
(sLex, Neu5Ac alpha 2-3Gal beta 1-4[Fuc alpha 1-3]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-sLex neoglycoprotein, a
heparin-derived tetrasaccharide mixture inhibited 50% of L- and
P-selectin-Ig binding (IC50) at 200 +/- 40 mumol/L and 850 +/- 110 mumol/L,
respectively. A single hexasulfated tetrasaccharide (delta UA2S alpha
1-4GlcNS6S alpha 1-4IdoA2S alpha 1- 4GlcNS6S) was particularly active
against L- and P-selectin-Ig (IC50 = 46 +/- 5 mumol/L and 341 +/- 24
mumol/L). By comparison, the tetrasaccharide sLex 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.
Volume 82,
Issue 11,
pp. 3253-3258,
12/01/1993
Copyright © 1993 by The American Society of Hematology
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