title: Butein suppresses ICAM-1 expression through the inhibition of IκBα and c-Jun phosphorylation in TNF-α- and PMA-treated HUVECs.
abstract: Butein (3,4,2',4'-tetrahydroxychalcone), a flavonoid derivative, has been reported to show several biological actions, including anti-inflammatory and anti-cancer. However, the possible molecular mechanisms involved are poorly understood. Treatment of human umbilical vein endothelial cells (HUVECs) with butein significantly inhibited cell surface intercellular adhesion molecule-1 (ICAM-1) expression, ICAM-1 protein synthesis, and mRNA expression induced by tumor necrotic factor-α (TNF-α) and/or phorbol 12-myristate 13-acetate (PMA). Electrophoretic mobility shift assay revealed that butein blocked activation of transcription factors, nuclear factor-κB (NF-κB) and activator protein-1 (AP-1), induced by TNF-α and PMA. Moreover, butein abolished TNF-α- and PMA-induced IκBα phosphorylation, which participates in NF-κB activation, and PMA-induced phosphorylation of c-Jun, a subunit composed of AP-1. In vitro, butein inhibited the phosphorylation of c-Jun, binding to GST beads, mediated by JNK isolated from PMA-treated cells. The inhibitory action of butein on the JNK-mediated in vitro c-Jun phosphorylation was abrogated in the presence of ATP. These results indicate that in HUVECs, butein suppresses the expression of ICAM-1 mRNA and protein through the inhibition of the activation of NF-κB and AP-1 induced by TNF-α and PMA, that the inhibitory action of butein on NF-κB activation results from the inhibition of IκBα phosphorylation by IκB kinase (IKK), and that the inactivation of PMA-activated AP-1 by butein is due to the blocking of JNK-mediated c-Jun phosphorylation through the inhibition of ATP binding.
authors.affiliation: Laboratory of Analytical Pharmacology, Faculty of Pharmacy, Meijo University, Nagoya 468-8503, Japan. Electronic address: kojima@meijo-u.ac.jp.
authors.forename: Ryoji
authors.initials: R
authors.lastname: Kojima
authors.affiliation: Laboratory of Analytical Pharmacology, Faculty of Pharmacy, Meijo University, Nagoya 468-8503, Japan.
authors.forename: Masanao
authors.initials: M
authors.lastname: Kawachi
authors.affiliation: Laboratory of Analytical Pharmacology, Faculty of Pharmacy, Meijo University, Nagoya 468-8503, Japan.
authors.forename: Mikio
authors.initials: M
authors.lastname: Ito
mesh_terms: D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D002478:Cells, Cultured; D047188:Chalcones / Q000494:pharmacology*; D042783:Endothelial Cells / Q000187:drug effects* / Q000502:physiology; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D020672:I-kappa B Proteins / Q000378:metabolism; D007165:Immunosuppression Therapy; D018799:Intercellular Adhesion Molecule-1 / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D016755:Proto-Oncogene Proteins c-jun / Q000235:genetics / Q000378:metabolism*; D013755:Tetradecanoylphorbol Acetate / Q000031:analogs & derivatives / Q000276:immunology; D018808:Transcription Factor AP-1 / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology; D014470:Umbilical Cord / Q000166:cytology
chemical_list: D000893:Anti-Inflammatory Agents; D047188:Chalcones; D020672:I-kappa B Proteins; D016755:Proto-Oncogene Proteins c-jun; D018808:Transcription Factor AP-1; D014409:Tumor Necrosis Factor-alpha; D018799:Intercellular Adhesion Molecule-1; C040918:butein; C020922:4-O-methyl-12-O-tetradecanoylphorbol 13-acetate; D013755:Tetradecanoylphorbol Acetate
keywords: Butein; ICAM-1; IκB; PMA; c-Jun