Inositol polyanions. Noncarbohydrate inhibitors of L- and P-selectin that block inflammation

O. Cecconi, R. M. Nelson, W. G. Roberts, K. Hanasaki, G. Mannori, Carsten Schultz, T. R. Ulich, A. Aruffo, M. P. Bevilacqua

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66 Scopus citations

Abstract

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 languageEnglish (US)
Pages (from-to)15060-15066
Number of pages7
JournalJournal of Biological Chemistry
Volume269
Issue number21
Publication statusPublished - 1994
Externally publishedYes

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ASJC Scopus subject areas

  • Biochemistry

Cite this

Cecconi, O., Nelson, R. M., Roberts, W. G., Hanasaki, K., Mannori, G., Schultz, C., ... Bevilacqua, M. P. (1994). Inositol polyanions. Noncarbohydrate inhibitors of L- and P-selectin that block inflammation. Journal of Biological Chemistry, 269(21), 15060-15066.