Selectins are cell adhesion molecules known to support the initial attachment of leukocytes to inflamed vascular endothelium through their recognition of carbohydrate ligands such as the tetrasaccharide sialyl Lewis(x) (Neu5Acα2-3Galβ1-4(Fucα1-3)GlcNAc-). In the present study, we describe the inhibition of L- and P- selectin function by inositol polyanions, simple 6-carbon ring structures that have multiple ester-linked phosphate or sulfate groups. In a purified component competition assay, binding of L- and P-selectin-Ig fusion proteins to immobilized bovine serum albumin-sialyl Lewis(x) neoglycoprotein was inhibited by inositol hexakisphosphate (InsP6, IC50 = 2.1 ± 1.4 μM and 160 ± 40 μM), by inositol pentakisphosphate (InsP5, IC50 = 1.4 ± 0.2 and 260 ± 40 μM), and by inositol hexakissulfate (InsS6, IC50 = 210 ± 80 μM and 2.8 ± 0.9 mM); E-selectin-Ig binding was unaffected. Inositol polyanions diminished the adhesion of LS180 colon carcinoma cells to plates coated with L- and P- selectin-Ig but not with E-selectin-Ig. Inositol polyanions blocked polymorphonuclear leukocyte (PMN) adhesion to COS cells expressing recombinant transmembrane P-selectin but not to those expressing E-selectin. In addition, inositol polyanions diminished PMN adhesion to activated endothelial cells under rotation-induced shear stress, a process known to require L-selectin function. In vivo, the effects of inositol polyanions were studied in two murine models of acute inflammation. Intravenously administered InsP6 (two doses of 40 μmol/kg) inhibited PMN accumulation in thioglycolate-induced inflammation (55 ± 10% inhibition) and in zymosan- induced inflammation (61 ± 4% inhibition). InsP5 and InsS6 also inhibited inflammation in these models, although higher doses were required for InsS6. In conclusion, inositol polyanions are noncarbohydrate small molecules that inhibit L- and P-selectin function in vitro and inflammation in vivo.
|Original language||English (US)|
|Number of pages||7|
|Journal||Journal of Biological Chemistry|
|Publication status||Published - 1994|
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