title: Flavonoids inhibit cytokine-induced endothelial cell adhesion protein gene expression.
abstract: Treatment of human endothelial cells with cytokines such as interleukin-1, tumor necrosis factor-alpha (TNF-alpha) or interferon-gamma induces the expression of specific leukocyte adhesion molecules on the endothelial cell surface. Interfering with either leukocyte adhesion or adhesion protein upregulation is an important therapeutic target as evidenced by the potent anti-inflammatory actions of neutralizing antibodies to these ligands in various animal models and in patients. In the present study we report that cotreatment of human endothelial cells with 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-dependent, reversible effect on adhesion protein expression as well as inhibiting adhesion protein upregulation at the transcriptional level. Apigenin also inhibited IL-1 alpha-induced prostaglandin synthesis and TNF-alpha-induced IL-6 and IL-8 production, suggesting that the hydroxyflavones may act as general inhibitors of cytokine-induced gene expression. Although apigenin did not inhibit TNF-alpha-induced nuclear translocation 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 transcriptional activation. Adhesion of leukocytes to cytokine-treated endothelial cells was blocked in endothelial cells cotreated with apigenin. Finally, apigenin demonstrated potent anti-inflammatory activity in carrageenan induced rat paw edema and delayed type hypersensitivity in the mouse. We conclude that flavonoids offer important therapeutic potential for the treatment of a variety of inflammatory diseases involving an increase in leukocyte adhesion and trafficking.
authors.affiliation: Institute for Bone and Joint Disease and Cancer, Bayer Corporation, West Haven, Connecticut 06516, USA.
authors.forename: M E
authors.initials: ME
authors.lastname: Gerritsen
authors.forename: W W
authors.initials: WW
authors.lastname: Carley
authors.forename: G E
authors.initials: GE
authors.lastname: Ranges
authors.forename: C P
authors.initials: CP
authors.lastname: Shen
authors.forename: S A
authors.initials: SA
authors.lastname: Phan
authors.forename: G F
authors.initials: GF
authors.lastname: Ligon
authors.forename: C A
authors.initials: CA
authors.lastname: Perry
mesh_terms: D001483:Base Sequence; D015815:Cell Adhesion Molecules / Q000235:genetics* / Q000378:metabolism; D020843:Chamomile; D016207:Cytokines / Q000494:pharmacology*; D003587:Cytomegalovirus / Q000235:genetics; D004247:DNA / Q000378:metabolism; D019040:E-Selectin; D005419:Flavonoids / Q000737:chemistry / Q000494:pharmacology*; D015870:Gene Expression / Q000187:drug effects*; D006801:Humans; D007249:Inflammation / Q000139:chemically induced; D018799:Intercellular Adhesion Molecule-1 / Q000235:genetics* / Q000378:metabolism; D015335:Molecular Probes / Q000235:genetics; D008969:Molecular Sequence Data; D016328:NF-kappa B / Q000235:genetics / Q000502:physiology; D009822:Oils, Volatile / Q000494:pharmacology; D010946:Plants, Medicinal; D011401:Promoter Regions, Genetic / Q000187:drug effects; D012333:RNA, Messenger / Q000378:metabolism; D013329:Structure-Activity Relationship; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D019010:Vascular Cell Adhesion Molecule-1
chemical_list: D015815:Cell Adhesion Molecules; D016207:Cytokines; D019040:E-Selectin; D005419:Flavonoids; D015335:Molecular Probes; D016328:NF-kappa B; D009822:Oils, Volatile; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D019010:Vascular Cell Adhesion Molecule-1; D018799:Intercellular Adhesion Molecule-1; D004247:DNA