title: Contribution of alpha4beta1 integrin to the antiallergic effect of levocabastine.
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.
authors.affiliation: Department of Medicine, Health Science Campus, University of Toledo, OH, USA.
authors.forename: Ahmed R
authors.initials: AR
authors.lastname: Qasem
authors.forename: Claudio
authors.initials: C
authors.lastname: Bucolo
authors.forename: Monica
authors.initials: M
authors.lastname: Baiula
authors.forename: Antonino
authors.initials: A
authors.lastname: Spartà
authors.forename: Paolo
authors.initials: P
authors.lastname: Govoni
authors.forename: Andrea
authors.initials: A
authors.lastname: Bedini
authors.forename: Domenico
authors.initials: D
authors.lastname: Fascì
authors.forename: Santi
authors.initials: S
authors.lastname: Spampinato
mesh_terms: D000818:Animals; D018926:Anti-Allergic Agents / Q000737:chemistry / Q000378:metabolism*; D002478:Cells, Cultured; D002744:Chlorpheniramine / Q000737:chemistry / Q000378:metabolism; D006168:Guinea Pigs; D039563:Histamine H1 Antagonists, Non-Sedating / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D039041:Integrin alpha4beta1 / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000378:metabolism; D019169:Jurkat Cells; D008297:Male; D010880:Piperidines / Q000737:chemistry / Q000378:metabolism*; D011485:Protein Binding / Q000502:physiology
chemical_list: D018926:Anti-Allergic Agents; D039563:Histamine H1 Antagonists, Non-Sedating; D039041:Integrin alpha4beta1; D010880:Piperidines; D002744:Chlorpheniramine; C047340:levocabastine