| Summary: | 碩士 === 國立臺灣大學 === 藥理學研究所 === 90 === The intercellular adheiosn molecule-1 (ICAM-1) has been implicated in the process of inflammation and atherosclerosis. Flavonoids which are naturally occurring polyphenolic compounds with a wide distribution throughout the plant kingdom, have potent anti-inflammatory property. In the present study, we investigated the effect of various flavonoids on the TNF-a-induced ICAM-1 expression in A549 epithelial cells. Pretreatment of cells with flavonols (quercetin and kaempferol) and flavones (flavone, chrysin, apigenin, luteolin, baicalein and baicalin) inhibited the TNF-a-stimulated ICAM-1 expression. Of these compounds tested, kaempferol, chrysin, apigenin and luteolin were active inhibitors with IC50 less than 2 mM. These four flavonoids also reduced adhesion of U937 cells to TNF-a-activated A549 epithelial cells. RT-PCR analysis demonstrated that they blocked ICAM-1 mRNA expression induced by TNF-a. The TNF-a-induced ICAM-1 promoter activity was attenuated by these four flavonoids. Among them, apigenin and luteolin were more potent than kaempferol and chrysin in inhibiting IKK activity, IkBa degradation, specific NF-kB DNA-protein binding and NF-kB luciferase activity. The ICAM-1 promter activity induced by TNF-a was attenuated using ICAM-1 construct lacking the TRE site, indicating that TRE site also plays an important role in TNF-a-induced ICAM-1 expression. AP-1 specific DNA-protein binding activity was increased by TNF-a and supershift assay demonstrated c-jun and c-fos component in AP-1 complex. These four flavonoids significantly inhibited TNF-a-induced AP-1 promoter activity, AP-1 specific DNA-protein binding , induction of c-jun or c-fos mRNA, and JNK or p38 activity. These results suggest that kaempferol and chrysin downregulate TNF-a- induced ICAM-1 expression via inhibition of AP-1 activation, while apigenin and luteolin acting via inhibition of both AP-1 and NF-kB. Kaempferol, apigenin and luteolin also suppressed TNF-a- or TPA-induced COX-2 expression in NCI-H292 epithelial cells, indicating that inhibition of ICAM-1 and COX-2 expression by apigenin and related flavonoids may be important in the prevention of inflammation and carcinogenesis.
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