FLAVONOIDS INHIBIT CYTOKINE-INDUCED ENDOTHELIAL-CELL ADHESION PROTEINGENE-EXPRESSION

Treatment of human endothelial cells with cytokines such as interleuki n-l, tumor necrosis factor-alpha (TNF-alpha) or interferon-gamma induc es the expression of specific leukocyte adhesion molecules on the endo thelial cell surface. Interfering with either leukocyte adhesion or ad hesion protein upregulation is an important therapeutic target as evid enced by the potent anti-inflammatory actions of neutralizing antibodi es to these ligands in various animal models and in patients. In the p resent study we report that cotreatment of human endothelial cells wit h certain hydroxyflavones and flavanols blocks cytokine-induced ICAM-1 , VCAM-1, and E-selectin expression on human endothelial cells. One of the most potent flavones, apigenin, exhibited a dose- and time-depend ent, reversible effect on adhesion protein expression as well as inhib iting adhesion protein upregulation at the transcriptional level. Apig enin also inhibited IL-1 alpha-induced prostaglandin synthesis and TNF -alpha-induced IL-6 and IL-8 production, suggesting that the hydrxyofl avones may act as general Inhibitors of cytokine-induced gene expressi on Although apigenin did not inhibit TNF-alpha induced nuclear translo cation of NF-kappa B(p50(NFKB1)/p65(RelA)) we found this flavonoid did inhibit TNF-alpha induced beta-galactosidase activity in SW480 cells stably transfected with a beta-galactosidase reporter construct driven by four NF-kappa B elements, suggesting an action on NF-kappa B trans criptional activation Adhesion of leukocytes to cytokine-treated endot helial cells was blocked in endothelial cells cotreated with apigenin. Finally, apigenin demonstrated potent anti-inflammatory activity in c arrageenan induced rat paw edema and delayed type hypersensitivity in the mouse. We conclude that flavonoids offer important therapeutic pot ential for the treatment of a variety of inflammatory diseases involvi ng an increase in leukocyte adhesion and trafficking.