A Novel Cell Adhesion Inhibitor, K-7174, Reduces the Endothelial VCAM-1 Induction by Inflammatory Cytokines, Acting through the Regulation of GATA

Abstract

A novel inhibitor for the adhesion of monocytes to cytokine-stimulated endothelial cells, K-7174, was selected by an assay system using the cultured human monocytic cells and human endothelial cells. K-7174 inhibited the expression of vascular cell adhesion molecule-1 (VCAM-1) induced by either tumor necrosis factor α or interleukin-1β, without affecting the induction of intercellular adhesion molecule-1 or E-selectin. K-7174 had no effect on the stability of VCAM-1 mRNA. Electrophoretic mobility shift assay revealed that its inhibitory effect on VCAM-1 induction was mediated by an effect on the binding to the GATA motifs in the VCAM-1 gene promoter region. K-7174 did not influence the binding to any of the following binding motifs: octamer binding protein, AP-1, SP-1, ets, NFκB, or interferon regulatory factor. These results suggest that the regulation of GATA binding may become a new target for anti-inflammatory drug development, acting through a mechanism independent from NFκB activity.