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Flavonoids Inhibit Tumor Necrosis Factor--Induced Up-Regulation of Intercellular Adhesion Molecule-1 (ICAM-1) in Respiratory Epithelial Cells through Activator Protein-1 and Nuclear Factor-B: Structure-Activity Relationships

Department of Pharmacology, College of Medicine, National Taiwan University, Taipei, Taiwan

Intercellular adhesion molecule-1 (ICAM-1) has been implicated in the processes of inflammation and carcinogenesis. Flavonoids, which are polyphenolic compounds with a wide distribution throughout the plant kingdom, have potent anti-inflammatory properties. We investigated the effects of flavonols (kaempferol, quercetin, and myricetin) and flavones (flavone, chrysin, apigenin, luteolin, baicalein, and baicalin) on the tumor necrosis factor- (TNF-)-stimulated ICAM-1 expression. Among those flavonoids tested, kaempferol, chrysin, apigenin, and luteolin are active inhibitors of ICAM-1 expression. Additional experiments suggested that apigenin and luteolin were actively inhibiting the IB kinase (IKK) activity, the IB degradation, the nuclear factor-B (NF-B) DNA-protein binding, and the NF-B luciferase activity. TNF--induced ICAM-1 promoter activity was attenuated using an activator protein-1 (AP-1) site deletion mutant, indicating the involvement of AP-1 in ICAM-1 expression. AP-1-specific DNA-protein binding activity was increased by TNF-, and the supershift assay identified the components of c-fos and c-jun. Extracellular signal-regulated kinase (ERK) and p38 were involved in the c-fos mRNA expression, and c-Jun NH₂-terminal kinase (JNK) was involved in the c-jun mRNA expression. All three mitogen-activated protein kinase (MAPK) activities were inhibited by apigenin and luteolin. In comparison, kaempferol and chrysin only inhibited the JNK activity. The inhibitory effects of apigenin and luteolin on ICAM-1 expression are mediated by the sequential attenuation of the three MAPKs activities, the c-fos and c-jun mRNA expressions, and the AP-1 transcriptional activity. IKK/NF-B pathway is also involved; however, kaempferol- and chrysin-mediated inhibitions are primarily executed through the attenuation of JNK activity, c-jun mRNA expression, and AP-1 activity. The structure-activity relationships are also explored, and the important role of –OH group at positions 5 and 7 of A ring and at position 4 of B ring is noted. Finally, our results suggested that AP-1 seems to play a more significant role than NF-B in the flavonoid-induced ICAM-1 inhibition.

Address correspondence to: Dr. Ching-Chow Chen, Department of Pharmacology, College of Medicine, National Taiwan University, No.1, Jen-Ai Road, Section 1, Taipei 10018, Taiwan. E-mail: ccchen{at}ha.mc.ntu.edu.tw

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