Inhibition of adhesion of human neutrophils and eosinophils to P- selectin by the sialyl Lewis(x) antagonist TBC1269: Preferential activity against neutrophil adhesion in vitro

Kelly L. Davenpeck, Kurt L. Berens, Richard A F Dixon, Brian Dupre, Bruce S. Bochner

Research output: Contribution to journalArticle

Abstract

Background: Leukocyte rolling on vascular endothelium is mediated by selectins and their carbohydrate-containing counterligands. The tetrasaccharide sialyl Lewis(x) (sLe(x)) binds to all 3 selectins, so compounds that mimic sLe(x) are potential antagonists. Objective: Our purpose was to examine the ability of the sLe(x) mimetic TBC1269 to inhibit binding of human neutrophils and eosinophils to P-selectin. Methods: Expression of the primary P-selectin ligand, P-selectin glycoprotein ligand-1 (PSGL-1), was examined on neutrophils and eosinophils, and their adhesion to immobilized P- selectin was examined under both static and dynamic conditions in the presence and absence of TBC1269. Results: Neutrophils and eosinophils expressed PSGL-1, with eosinophils expressing about twice as much as neutrophils. In the absence of TBC1269, both cell types adhered avidly to P- selectin under static and dynamic conditions. For neutrophils, preincubation of P-selectin-coated plates with TBC1269 (1 to 1000 μg/mL) resulted in concentration-dependent decreases in neutrophil adhesion, with significant inhibition seen at concentrations ≥100 μg/mL. Eosinophil adhesion to P- selectin was more refractory to inhibition by TBC1269 and was only partially inhibited at the highest concentration tested (1000 μg/mL). Two structurally related control compounds, TBC1900 and TBC746, had no effect when tested at similar concentrations. Conclusion: These data indicate that an sLe(x) mimetic can exhibit cell type-specific differences in potencies with respect to antagonism of P-selectin adhesion. Although this may in part be the result of differences in PSGL-1 expression, the discrepancy in potencies may also be due to other differences, including carbohydrate composition and binding affinity of PSGL-1.

Original languageEnglish (US)
Pages (from-to)769-775
Number of pages7
JournalThe Journal of Allergy and Clinical Immunology
Volume105
Issue number4
StatePublished - 2000

Fingerprint

P-Selectin
Eosinophils
Neutrophils
Selectins
Carbohydrates
Leukocyte Rolling
Aptitude
Vascular Endothelium
In Vitro Techniques
5-acetylneuraminyl-(2-3)-galactosyl-(1-4)-(fucopyranosyl-(1-3))-N-acetylglucosamine
Inhibition (Psychology)
Ligands
P-selectin ligand protein

Keywords

  • Adhesion
  • Antagonist
  • Eosinophils
  • Glycomimetic
  • Neutrophils
  • P- selectin
  • PSGL1
  • Sialyl Lewis(x)

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

Cite this

Inhibition of adhesion of human neutrophils and eosinophils to P- selectin by the sialyl Lewis(x) antagonist TBC1269 : Preferential activity against neutrophil adhesion in vitro. / Davenpeck, Kelly L.; Berens, Kurt L.; Dixon, Richard A F; Dupre, Brian; Bochner, Bruce S.

In: The Journal of Allergy and Clinical Immunology, Vol. 105, No. 4, 2000, p. 769-775.

Research output: Contribution to journalArticle

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abstract = "Background: Leukocyte rolling on vascular endothelium is mediated by selectins and their carbohydrate-containing counterligands. The tetrasaccharide sialyl Lewis(x) (sLe(x)) binds to all 3 selectins, so compounds that mimic sLe(x) are potential antagonists. Objective: Our purpose was to examine the ability of the sLe(x) mimetic TBC1269 to inhibit binding of human neutrophils and eosinophils to P-selectin. Methods: Expression of the primary P-selectin ligand, P-selectin glycoprotein ligand-1 (PSGL-1), was examined on neutrophils and eosinophils, and their adhesion to immobilized P- selectin was examined under both static and dynamic conditions in the presence and absence of TBC1269. Results: Neutrophils and eosinophils expressed PSGL-1, with eosinophils expressing about twice as much as neutrophils. In the absence of TBC1269, both cell types adhered avidly to P- selectin under static and dynamic conditions. For neutrophils, preincubation of P-selectin-coated plates with TBC1269 (1 to 1000 μg/mL) resulted in concentration-dependent decreases in neutrophil adhesion, with significant inhibition seen at concentrations ≥100 μg/mL. Eosinophil adhesion to P- selectin was more refractory to inhibition by TBC1269 and was only partially inhibited at the highest concentration tested (1000 μg/mL). Two structurally related control compounds, TBC1900 and TBC746, had no effect when tested at similar concentrations. Conclusion: These data indicate that an sLe(x) mimetic can exhibit cell type-specific differences in potencies with respect to antagonism of P-selectin adhesion. Although this may in part be the result of differences in PSGL-1 expression, the discrepancy in potencies may also be due to other differences, including carbohydrate composition and binding affinity of PSGL-1.",
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T1 - Inhibition of adhesion of human neutrophils and eosinophils to P- selectin by the sialyl Lewis(x) antagonist TBC1269

T2 - Preferential activity against neutrophil adhesion in vitro

AU - Davenpeck, Kelly L.

AU - Berens, Kurt L.

AU - Dixon, Richard A F

AU - Dupre, Brian

AU - Bochner, Bruce S.

PY - 2000

Y1 - 2000

N2 - Background: Leukocyte rolling on vascular endothelium is mediated by selectins and their carbohydrate-containing counterligands. The tetrasaccharide sialyl Lewis(x) (sLe(x)) binds to all 3 selectins, so compounds that mimic sLe(x) are potential antagonists. Objective: Our purpose was to examine the ability of the sLe(x) mimetic TBC1269 to inhibit binding of human neutrophils and eosinophils to P-selectin. Methods: Expression of the primary P-selectin ligand, P-selectin glycoprotein ligand-1 (PSGL-1), was examined on neutrophils and eosinophils, and their adhesion to immobilized P- selectin was examined under both static and dynamic conditions in the presence and absence of TBC1269. Results: Neutrophils and eosinophils expressed PSGL-1, with eosinophils expressing about twice as much as neutrophils. In the absence of TBC1269, both cell types adhered avidly to P- selectin under static and dynamic conditions. For neutrophils, preincubation of P-selectin-coated plates with TBC1269 (1 to 1000 μg/mL) resulted in concentration-dependent decreases in neutrophil adhesion, with significant inhibition seen at concentrations ≥100 μg/mL. Eosinophil adhesion to P- selectin was more refractory to inhibition by TBC1269 and was only partially inhibited at the highest concentration tested (1000 μg/mL). Two structurally related control compounds, TBC1900 and TBC746, had no effect when tested at similar concentrations. Conclusion: These data indicate that an sLe(x) mimetic can exhibit cell type-specific differences in potencies with respect to antagonism of P-selectin adhesion. Although this may in part be the result of differences in PSGL-1 expression, the discrepancy in potencies may also be due to other differences, including carbohydrate composition and binding affinity of PSGL-1.

AB - Background: Leukocyte rolling on vascular endothelium is mediated by selectins and their carbohydrate-containing counterligands. The tetrasaccharide sialyl Lewis(x) (sLe(x)) binds to all 3 selectins, so compounds that mimic sLe(x) are potential antagonists. Objective: Our purpose was to examine the ability of the sLe(x) mimetic TBC1269 to inhibit binding of human neutrophils and eosinophils to P-selectin. Methods: Expression of the primary P-selectin ligand, P-selectin glycoprotein ligand-1 (PSGL-1), was examined on neutrophils and eosinophils, and their adhesion to immobilized P- selectin was examined under both static and dynamic conditions in the presence and absence of TBC1269. Results: Neutrophils and eosinophils expressed PSGL-1, with eosinophils expressing about twice as much as neutrophils. In the absence of TBC1269, both cell types adhered avidly to P- selectin under static and dynamic conditions. For neutrophils, preincubation of P-selectin-coated plates with TBC1269 (1 to 1000 μg/mL) resulted in concentration-dependent decreases in neutrophil adhesion, with significant inhibition seen at concentrations ≥100 μg/mL. Eosinophil adhesion to P- selectin was more refractory to inhibition by TBC1269 and was only partially inhibited at the highest concentration tested (1000 μg/mL). Two structurally related control compounds, TBC1900 and TBC746, had no effect when tested at similar concentrations. Conclusion: These data indicate that an sLe(x) mimetic can exhibit cell type-specific differences in potencies with respect to antagonism of P-selectin adhesion. Although this may in part be the result of differences in PSGL-1 expression, the discrepancy in potencies may also be due to other differences, including carbohydrate composition and binding affinity of PSGL-1.

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KW - Antagonist

KW - Eosinophils

KW - Glycomimetic

KW - Neutrophils

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KW - PSGL1

KW - Sialyl Lewis(x)

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