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Inhibition of interleukin-12 production in mouse macrophagesvia decreased nuclear factor-κB DNA binding activity by myricetin, a naturally occurring flavonoid

Archives of Pharmacal Research volume 28, pages 274–279 (2005)Cite this article

Abstract

Pharmacological inhibition of interleukin-12 (IL-12) production may be a therapeutic strategy for preventing the development and progression of disease in experimental models of autoimmunity. In this study, the effects of myricetin, a naturally occurring flavonoid present in fruits, vegetables and medicinal herbs, on the production of IL-12 were investigated in mouse macrophages stimulated with lipopolysaccharide (LPS). Myricetin significantly inhibited the LPS-induced IL-12 production from both primary macrophages and the RAW264.7 monocytic cell-line in a dose-dependent manner. The effect of myricetin on IL-12 gene promoter activation was analyzed by transfecting RAW264.7 cells with IL-12 gene promoter/luciferase constructs. The repressive effect was mapped to a region in the IL-12 gene promoter containing a binding site for NF-κB. Furthermore, activation of macrophages by LPS resulted in markedly enhanced binding activity to the NF-κB site, which significantly decreased upon addition of myricetin, indicating that myricetin inhibited IL-12 production in LPS-activated macrophagesvia the down-regulation of NF-κB binding activity.

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References

  • Adorini, L., Interleukin-12, a key cytokine in Th1-mediated autoimmune diseases.Cell Mol. Life Sci., 55, 1610–1625 (1999).

    Article  PubMed  CAS  Google Scholar 

  • Chen, C. C., Chow, M. P., Huang, W. C., Lin, Y. C., and Chang, Y. J., Flavonoids inhibit tumor necrosis factor-alpha-induced up-regulation of intercellular adhesion molecule-1 (ICAM-1) in respiratory epithelial cells through activator protein-1 and nuclear factor-κB: structure-activity relationships.Mol. Pharmacol., 66, 683–693 (2004).

    Article  PubMed  CAS  Google Scholar 

  • Chu, S. C., Hsieh, Y. S., and Lin, J. Y., Inhibitory effects of flavonoids on Moloney murine leukemia virus reverse transcriptase activity.J. Nat. Prod., 55, 179–183 (1992).

    Article  PubMed  CAS  Google Scholar 

  • Constantinescu, C. S., Goodman, D. B., and Ventura, E. S., Captopril and lisinopril suppress production of interleukin-12 by human peripheral blood mononuclear cells.Immunol. Lett., 62, 25–31 (1998).

    Article  PubMed  CAS  Google Scholar 

  • D’Ambrosio, D., Cippitelli, M., Cocciolo, M. G., Mazzeo, D., Di Lucia, P., Lang, R., Sinigaglia, F., and Panina-Bordignon, P., Inhibition of IL-12 production by 1,25-dihydroxyvitamin D3. Involvement of NF-κB downregulation in transcriptional repression of the p40 gene.J. Clin. Invest., 101, 252–262 (1998).

    Article  PubMed  CAS  Google Scholar 

  • DeKruyff, R. H., Fang, Y., and Umetsu, D. T., Corticosteroids enhance the capacity of macrophages to induce Th2 cytokine synthesis in CD4+ lymphocytes by inhibiting IL-12 production.J. Immunol., 160, 2231–2237 (1998).

    PubMed  CAS  Google Scholar 

  • Dignam, J. D., Lebovitz, R. M., and Roeder, R. G., Accurate transcription initiation by RNA polymerase II in a soluble extract from isolated mammalian nuclei.Nucleic Acids Res., 11, 1475–1489 (1993).

    Article  Google Scholar 

  • Falcone, M. and Sarvetnick, N., Cytokines that regulate autoimmune responses.Curr. Opin. Immunol., 11, 670–676 (1999).

    Article  PubMed  CAS  Google Scholar 

  • Gri, G., Savio, D., Trinchieri, G., and Ma, X., Synergistic regulation of the human interleukin-12 p40 promoter by NF-κB and Ets transcription factors in Epstein-Barr virus-transformed B cells and macrophages.J. Biol. Chem., 273, 6431–6438 (1998).

    Article  PubMed  CAS  Google Scholar 

  • Joo, S. S., Chang, J. K., Park, J. H., Kang, H. C., and Lee, D. I., Immunoactivation of lectin-conjugated praecoxin A on IL-6, IL-12 expression.Arch. Pharm. Res., 25, 954–963 (2002).

    Article  PubMed  CAS  Google Scholar 

  • Kang, B. Y., Chung, S. W., Cho, D., and Kim, T. S., Involvement of p38 mitogen-activated protein kinase in the induction of interleukin-12 p40 production in mouse macrophages by berberine, a benzodioxoloquinolizine alkaloid.Biochem. Pharmacol., 63, 1901–1910 (2002).

    Article  PubMed  CAS  Google Scholar 

  • Kang, B. Y., Chung, S. W., Im, S. Y., Hwang, S. Y., and Kim, T. S., Chloromethyl ketones inhibit interleukin-12 production in mouse macrophages stimulated with lipopolysaccharide.Immunol. Lett., 70, 135–138 (1999).

    Article  PubMed  CAS  Google Scholar 

  • Kang, K., Kubin, M., Cooper, K. D., Lessin, S. R., Trinchieri, G., and Rook, A. H., IL-12 synthesis by human Langerhans cells.J. Immunol., 156, 1402–1407 (1996).

    PubMed  CAS  Google Scholar 

  • Kim, T. S., Kang, B. Y., Lee, M. H., Choe, Y. K., and Hwang, S. Y., Inhibition of interleukin-12 production by auranofin, an anti-rheumatic gold compound, deviates CD4+ T cells from the Th1 to the Th2 pathway.Br. J. Pharmacol., 134, 571–578 (2001).

    Article  PubMed  CAS  Google Scholar 

  • Landolfi, R., Mower, R. L., and Steiner, M., Modification of platelet function and arachidonic acid metabolism by bioflavonoids. Structure-activity relations.Biochem. Pharmacol., 33, 1525–1530 (1984).

    Article  PubMed  CAS  Google Scholar 

  • Ma, X., Chow, J. M., Gri, G., Carra, G., Gerosa, F., Wolf, S. F., Dzialo, R., and Trinchieri, G., The interleukin 12 p40 gene promoter is primed by interferon-γ in monocytic cells.J. Exp. Med., 83, 147–157 (1996).

    Article  Google Scholar 

  • Ma, X. and Trinchieri, G., Regulation of interleukin-12 production in antigen-presenting cells.Adv. Immunol., 79, 55–92 (2001).

    Article  PubMed  CAS  Google Scholar 

  • Moller, D. R., Wysocka, W., Greenlee, B. M., Ma, X., Wahl, L., Flockhart, D. A., Trinchieri, G., and Karp, C. L., Inhibition of IL-12 production by thalidomide.J. Immunol., 159, 5157–1561 (1997).

    PubMed  CAS  Google Scholar 

  • Na, S. Y., Kang, B. Y., Chung, S. W., Han, S. J., Ma, X., Trinchieri, G., Im, S. Y., Lee, J. W., and Kim, T. S., Retinoids inhibit interleukin-12 production in macrophages through physical associations of retinoid X receptor and NF-κB.J. Biol. Chem., 274, 7674–7680 (1999).

    Article  PubMed  CAS  Google Scholar 

  • Ong, K. C. and Khoo, H. E., Effects of myricetin on glycemia and glycogen metabolism in diabetic rats.Life Sci., 67, 1695–1705 (2000).

    Article  PubMed  CAS  Google Scholar 

  • Panina-Bordignon, P., Mazzeo, D., Lucia, P. D., D’Ambrosio, D., Lang, R., Fabbri, L., Self, C., and Sinigaglia, F., β2-Agonists prevent Th1 development by selective inhibition of interleukin 12.J. Clin. Invest., 100, 1513–1519 (1997).

    Article  PubMed  CAS  Google Scholar 

  • Prud’homme, G. J., Gene therapy of autoimmune diseases with vectors encoding regulatory cytokines or inflammatory cytokine inhibitors.J. Gene Med., 2, 222–232 (2000).

    Article  PubMed  CAS  Google Scholar 

  • Ross, J. A. and Kasum, C. M., Dietary flavonoids: bioavailability, metabolic effects, and safety.Annu. Rev. Nutr., 22, 19–33 (2002).

    Article  PubMed  CAS  Google Scholar 

  • Theoharides, T. C., Alexandrakis, M., Kempuraj, D., and Lytinas, M., Anti-inflammatory actions of flavonoids and structural requirements for new design.Int. J. Immunopathol. Pharmacol., 14, 119–127 (2001).

    PubMed  CAS  Google Scholar 

  • Tsai, S. H., Liang, Y. C., Lin-Shiau, S. Y., and Lin, J. K., Suppression of TNFalpha-mediated NFκB activity by myricetin and other flavonoids through downregulating the activity of IKK in ECV304 cells.J. Cell Biochem., 74, 606–615 (1999).

    Article  PubMed  CAS  Google Scholar 

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Author notes

  1. Bok Yun Kang

    Present address: Department of Immunology and Infectious Diseases, Harvard School of Public Health, 02115, Boston, MA, USA

Authors and Affiliations

  1. Department of Life Science, Sookmyung Womens University, 140-742, Seoul, Korea

    Daeho Cho

  2. College of Pharmacy and Research Institute of Drug Development, Chonnam National University, 500-757, Gwangju, Korea

    Bok Yun Kang, Seung Hyun Kim, Daeho Cho & Tae Sung Kim

Authors
  1. Bok Yun Kang
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  2. Seung Hyun Kim
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  3. Daeho Cho
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  4. Tae Sung Kim
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Correspondence to Tae Sung Kim.

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Kang, B.Y., Kim, S.H., Cho, D. et al. Inhibition of interleukin-12 production in mouse macrophagesvia decreased nuclear factor-κB DNA binding activity by myricetin, a naturally occurring flavonoid. Arch Pharm Res 28, 274–279 (2005). https://doi.org/10.1007/BF02977791

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  • DOI: https://doi.org/10.1007/BF02977791

Key words

  • Myricetin
  • Interleukin-12
  • Macrophage
  • Nuclear factor-κB