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

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 Lewisx (Neu5Ac alpha 2-3Gal beta 1-4(Fuc alpha 1-3)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 microM and 160 +/- 40 microM), by inositol pentakisphosphate (InsP5, IC50 = 1.4 +/- 0.2 and 260 +/- 40 microM), and by inositol hexakissulfate (InsS6, IC50 = 210 +/- 80 microM 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 mumol/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.

• Authors: O Cecconi, R M Nelson, W G Roberts, K Hanasaki, G Mannori, C Schultz, T R Ulich, A Aruffo, M P Bevilacqua
• Journal: The Journal of biological chemistry (J Biol Chem) Vol. 269 Issue 21 Pg. 15060-6 (May 27 1994) ISSN: 0021-9258 [Print] United States
• PMID: 7515048 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Cell Adhesion Molecules
• Immunoglobulins
• Oligosaccharides
• P-Selectin
• Platelet Membrane Glycoproteins
• Polyelectrolytes
• Polymers
• Sialyl Lewis X Antigen
• polyanions
• L-Selectin
• Serum Albumin, Bovine
• Inositol

Topics

• Animals
• Carbohydrate Sequence
• Cell Adhesion (drug effects)
• Cell Adhesion Molecules (drug effects)
• Cells, Cultured
• Haplorhini
• Humans
• Immunoglobulins (metabolism)
• Inflammation (drug therapy, pathology)
• Inositol (chemistry, pharmacology, therapeutic use)
• L-Selectin
• Lung (immunology, pathology)
• Male
• Molecular Sequence Data
• Neutrophils (cytology)
• Oligosaccharides (metabolism)
• P-Selectin
• Peritoneal Cavity (pathology)
• Platelet Membrane Glycoproteins (antagonists & inhibitors)
• Polyelectrolytes
• Polymers (chemistry, pharmacology, therapeutic use)
• Serum Albumin, Bovine (metabolism)
• Sialyl Lewis X Antigen
• Tumor Cells, Cultured