Contribution of alpha4beta1 integrin to the antiallergic effect of levocabastine

Biochem Pharmacol. 2008 Sep 15;76(6):751-62. doi: 10.1016/j.bcp.2008.07.007. Epub 2008 Jul 15.

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.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anti-Allergic Agents / chemistry
  • Anti-Allergic Agents / metabolism*
  • Cells, Cultured
  • Chlorpheniramine / chemistry
  • Chlorpheniramine / metabolism
  • Guinea Pigs
  • Histamine H1 Antagonists, Non-Sedating / chemistry
  • Histamine H1 Antagonists, Non-Sedating / metabolism
  • Humans
  • Integrin alpha4beta1 / antagonists & inhibitors
  • Integrin alpha4beta1 / chemistry*
  • Integrin alpha4beta1 / metabolism
  • Jurkat Cells
  • Male
  • Piperidines / chemistry
  • Piperidines / metabolism*
  • Protein Binding / physiology

Substances

  • Anti-Allergic Agents
  • Histamine H1 Antagonists, Non-Sedating
  • Integrin alpha4beta1
  • Piperidines
  • Chlorpheniramine
  • levocabastine