The cell adhesion molecule intercellular adhesion molecule-1 (ICAM-1) plays a pivotal role in inflammatory responses. Quercetin (3,3',4',5,7-pentahydroxyflavone), a naturally occurring dietary flavonol, has potent anti-inflammatory properties. The effect of quercetin on ICAM-1 expression induced by agonists phorbol 12-myristate 13-acetate (PMA) and tumor necrosis factor-alpha (TNF-alpha) in human endothelial cell line ECV304 (ECV) was investigated. Quercetin treatment downregulated both PMA- and TNF-alpha-induced surface expression, as well as the ICAM-1 mRNA levels, in ECV cells in a dose-dependent (10-50 microM) manner. Quercetin had no effect on PMA- or TNF-alpha-induced nuclear factor-kappaB (NF-kappaB) activation. However, under similar conditions a remarkable dose-dependent downregulation of activator protein-1 (AP-1) activation was observed. This decrease in AP-1 activation was observed to be associated with the inhibitory effects of quercetin on the c-Jun NH2-terminal kinase (JNK) pathway. These results suggest that quercetin downregulates both PMA- and TNF-alpha-induced ICAM-1 expression via inhibiting both AP-1 activation and the JNK pathway.