Article

Contribution of alpha4beta1 integrin to the antiallergic effect of levocabastine.

Department of Medicine, Health Science Campus, University of Toledo, OH, USA.
Biochemical pharmacology (impact factor: 4.25). 10/2008; 76(6):751-62. DOI:10.1016/j.bcp.2008.07.007 pp.751-62
Source: PubMed

ABSTRACT Levocabastine is an antiallergic drug acting as a histamine H1-receptor antagonist. In allergic conjunctivitis (AC), it may also antagonize up-regulation of the intercellular adhesion molecule-1 (ICAM-1) expressed on epithelial conjunctival cells. However, little is known about its effects on eosinophils, important effector cells in AC. The adhesion molecule integrin alpha(4)beta(1) is expressed in eosinophils; it interacts with the vascular cell adhesion molecule-1 (VCAM-1) and fibronectin (FN) in vascular endothelial cells and contributes to eosinophil activation and infiltration in AC. This study provides evidence that in a scintillation proximity assay levocabastine (IC(50) 406 microM), but not the first-generation antihistamine chlorpheniramine, displaced (125)I-FN binding to human integrin alpha(4)beta(1) and, in flow cytometry analysis, levocabastine antagonized the binding of a primary antibody to integrin alpha(4) expressed on the Jurkat cell surface. Levocabastine, but not chlorpheniramine, binds the alpha(4)beta(1) integrin and prevents eosinophil adhesion to VCAM-1, FN or human umbilical vascular endothelial cells (HUVEC) in vitro. Similarly, levocabastine affects alpha(L)beta(2)/ICAM-1-mediated adhesion of Jurkat cells. In a model of AC levocabastine eye drops reduced the clinical aspects of the late-phase reaction and the conjunctival expression of alpha(4)beta(1) integrin by reducing infiltrated eosinophils. We propose that blockade of integrin-mediated cell adhesion might be a target of the antiallergic action of levocabastine and may play a role in preventing eosinophil adhesion and infiltration in AC.

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Keywords

AC levocabastine eye
 
alpha(L)beta(2)/ICAM-1-mediated adhesion
 
antiallergic drug
 
conjunctival expression
 
effector cells
 
eosinophil activation
 
eosinophil adhesion
 
epithelial conjunctival cells
 
flow cytometry analysis
 
histamine H1-receptor antagonist
 
human umbilical vascular endothelial cells
 
infiltrated eosinophils
 
integrin-mediated cell adhesion
 
intercellular adhesion molecule-1
 
Jurkat cell surface
 
Jurkat cells
 
primary antibody
 
scintillation proximity assay levocabastine
 
vascular cell adhesion molecule-1
 
vascular endothelial cells