A novel cell adhesion inhibitor, K-7174, reduces the endothelial VCAM-1 induction by inflammatory cytokines, acting through the regulation of GATA

A novel inhibitor for the adhesion of monocytes to cytokine-stimulated endo thelial cells, K-7174, was selected by an assay system using the cultured h uman monocytic cells and human endothelial cells. K-7174 inhibited the expr ession of vascular cell adhesion molecule-1 (VCAM-1) induced by either tumo r necrosis factor alpha or interleukin-1 beta, without affecting the induct ion of intercellular adhesion molecule-1 or E-selectin. K-7174 had no effec t on the stability of VCAM-1 mRNA. Electrophoretic mobility shift assay rev ealed that its inhibitory effect on VCAM-1 induction was mediated by an eff ect 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, NF kappa B, or interferon regula tory 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 NF kappa B activity. (C) 2000 Academic Press.