Journal Article

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 and Jen-Kun Lin

in Carcinogenesis

Volume 20, issue 10, pages 1945-1952
Published in print October 1999 | ISSN: 0143-3334
Published online October 1999 | e-ISSN: 1460-2180 | DOI: http://dx.doi.org/10.1093/carcin/20.10.1945
Suppression of inducible cyclooxygenase and inducible nitric oxide synthase by apigenin and related flavonoids in mouse macrophages

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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.

Keywords: COX, cyclooxygenase; EGF, epidermal growth factor; EGCG, (–)-epigallocatechin-3-gallate; EIA, enzyme immunoassay; EMSA, electrophoretic mobility shift assay; iNOS, inducible nitric oxide synthase; IkB, inhibitor kB; IKK, IkB kinase; IFN-γ, interferon-γ; GAPDH, glyceraldehyde 3-phosphate dehydrogenase; LPS, lipopolysaccharide; NF-kB, nuclear factor-kB; NO, nitric oxide; NOS, nitric oxide synthase; PGE2, prostaglandin E2.

Journal Article.  6293 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

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