TY - JOUR
T1 - Inositol Polyanions
T2 - Noncarbohydrate Inhibitors of L- and P-selectin that Block Inflammation
AU - Cecconi, Oliviero
AU - Nelson, Richard M.
AU - Roberts, W. Gregory
AU - Hanasaki, Kohji
AU - Mannori, Gianna
AU - Schultz, Carsten
AU - Ulich, Thomas R.
AU - Aruffo, Alejandro
AU - Bevilacqua, Michael P.
PY - 1994/5/27
Y1 - 1994/5/27
N2 - 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 Lewisx (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 Lewisx 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.
AB - 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 Lewisx (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 Lewisx 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.
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M3 - Article
C2 - 7515048
AN - SCOPUS:0028308735
SN - 0021-9258
VL - 269
SP - 15060
EP - 15066
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
IS - 21
ER -