Suppression of inducible cyclooxygenase and inducible nitric oxide synthase by apigenin and related flavonoids in mouse macrophages

Yu Chih Liang, Ying Tang Huang, Shu Huei Tsai, Shoei Yn Lin-Shiau, Chieh Fu Chen, Jen Kun Lin

Research output: Contribution to journalArticle

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Abstract

Prostaglandins biosynthesis and nitric oxide production have been implicated in the process of carcinogenesis and inflammation. In this study, we investigated the effect of various flavonoids and (-)-epigallocatechin-3-gallate on the activities of inducible cyclooxygenase (COX-2) and inducible nitric oxide synthase (iNOS) in lipopolysaccharide (LPS)-activated RAW 264.7 macrophages. Apigenin, genistein and kaempferol were markedly active inhibitors of transcriptional activation of COX-2, with IC50 <15 μM. In addition, apigenin and kaempferol were also markedly active inhibitors of transcriptional activation of iNOS, with IC50 <15 μM. Of those compounds tested, apigenin was the most potent inhibitor of transcriptional activation of both COX-2 and iNOS. Western and northern blot analyses demonstrated that apigenin significantly blocked protein and mRNA expression of COX-2 and iNOS in LPS-activated macrophages. Transient transfection experiments showed that LPS caused an ~4-fold increase in both COX-2 and iNOS promoter activities, these increments were suppressed by apigenin. Moreover, electrophoretic mobility shift assay (EMSA) experiments indicated that apigenin blocked the LPS-induced activation of nuclear factor-kB (NF-kB). The inhibition of NF-kB activation occurs through the prevention of inhibitor kB (IkB) degradation. Transient transfection experiments also showed that apigenin inhibited NF-kB-dependent transcriptional activity. Finally, we showed that apigenin could inhibit the IkB kinase activity induced by LPS or interferon-γ. The results of further studies suggest that suppression of transcriptional activation of COX-2 and iNOS by apigenin might mainly be mediated through inhibition of IkB kinase activity. This study suggests that modulation of COX-2 and iNOS by apigenin and related flavonoids may be important in the prevention of carcinogenesis and inflammation.

Original languageEnglish
Pages (from-to)1945-1952
Number of pages8
JournalCarcinogenesis
Volume20
Issue number10
DOIs
Publication statusPublished - 1999
Externally publishedYes

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Apigenin
Nitric Oxide Synthase Type II
Prostaglandin-Endoperoxide Synthases
Flavonoids
Macrophages
Lipopolysaccharides
Transcriptional Activation
Inhibitory Concentration 50
Transfection
Carcinogenesis
Phosphotransferases
Inflammation
Genistein
Electrophoretic Mobility Shift Assay
Cyclooxygenase 2
Northern Blotting
Interferons
Prostaglandins
Nitric Oxide
Western Blotting

ASJC Scopus subject areas

  • Cancer Research

Cite this

Suppression of inducible cyclooxygenase and inducible nitric oxide synthase by apigenin and related flavonoids in mouse macrophages. / Liang, Yu Chih; Huang, Ying Tang; Tsai, Shu Huei; Lin-Shiau, Shoei Yn; Chen, Chieh Fu; Lin, Jen Kun.

In: Carcinogenesis, Vol. 20, No. 10, 1999, p. 1945-1952.

Research output: Contribution to journalArticle

Liang, Yu Chih ; Huang, Ying Tang ; Tsai, Shu Huei ; Lin-Shiau, Shoei Yn ; Chen, Chieh Fu ; Lin, Jen Kun. / Suppression of inducible cyclooxygenase and inducible nitric oxide synthase by apigenin and related flavonoids in mouse macrophages. In: Carcinogenesis. 1999 ; Vol. 20, No. 10. pp. 1945-1952.
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AU - Chen, Chieh Fu

AU - Lin, Jen Kun

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AB - Prostaglandins biosynthesis and nitric oxide production have been implicated in the process of carcinogenesis and inflammation. In this study, we investigated the effect of various flavonoids and (-)-epigallocatechin-3-gallate on the activities of inducible cyclooxygenase (COX-2) and inducible nitric oxide synthase (iNOS) in lipopolysaccharide (LPS)-activated RAW 264.7 macrophages. Apigenin, genistein and kaempferol were markedly active inhibitors of transcriptional activation of COX-2, with IC50 <15 μM. In addition, apigenin and kaempferol were also markedly active inhibitors of transcriptional activation of iNOS, with IC50 <15 μM. Of those compounds tested, apigenin was the most potent inhibitor of transcriptional activation of both COX-2 and iNOS. Western and northern blot analyses demonstrated that apigenin significantly blocked protein and mRNA expression of COX-2 and iNOS in LPS-activated macrophages. Transient transfection experiments showed that LPS caused an ~4-fold increase in both COX-2 and iNOS promoter activities, these increments were suppressed by apigenin. Moreover, electrophoretic mobility shift assay (EMSA) experiments indicated that apigenin blocked the LPS-induced activation of nuclear factor-kB (NF-kB). The inhibition of NF-kB activation occurs through the prevention of inhibitor kB (IkB) degradation. Transient transfection experiments also showed that apigenin inhibited NF-kB-dependent transcriptional activity. Finally, we showed that apigenin could inhibit the IkB kinase activity induced by LPS or interferon-γ. The results of further studies suggest that suppression of transcriptional activation of COX-2 and iNOS by apigenin might mainly be mediated through inhibition of IkB kinase activity. This study suggests that modulation of COX-2 and iNOS by apigenin and related flavonoids may be important in the prevention of carcinogenesis and inflammation.

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