Archives of Pharmacal Research

The Pharmaceutical Society of Korea (대한약학회)
권호 표지

Inhibition of Interleukin-12 Production in Mouse Macrophages via Decreased Nuclear $Factor-\kappaB$ DNA Binding Activity by Myricetin, a Naturally Occurring Flavonoid

  • Kang Bok Yun (College of Pharmacy and Research Institute of Drug Development, Chonnam National University) ;
  • Kim Seung Hyun (College of Pharmacy and Research Institute of Drug Development, Chonnam National University) ;
  • Cho Dae Ho (Department of Life Science, Sookmyung Womens University) ;
  • Kim Tae Sung (College of Pharmacy and Research Institute of Drug Development, Chonnam National University)
  • Published : 2005.03.01
Download PDF
⟨ Previous Next ⟩

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 LPS­induced 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-${\kappa}B$. Furthermore, activation of macrophages by LPS resulted in markedly enhanced binding activity to the NF-${\kappa}B$ site, which significantly decreased upon addition of myricetin, indicating that myricetin inhibited IL-12 production in LPS-activated macrophages via the down­regulation of NF-KB binding activity.

Keywords

References

  1. Adorini, L., Interleukin-12, a key cytokine in Th1-mediated autoimmune diseases. Cell Mol. Life Sci., 55, 1610-1625 (1999) https://doi.org/10.1007/s000180050400
  2. 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- $\kappa$B: structure-activity relationships. Mol. Pharmacol., 66, 683-693 (2004)
  3. 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) https://doi.org/10.1021/np50080a005
  4. 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) https://doi.org/10.1016/S0165-2478(98)00025-X
  5. 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 $D_3$, Involvement of NF-$\kappa$B downregulation in transcriptional repression of the p40 gene. J. Clin. Invest., 101, 252-262 (1998) https://doi.org/10.1172/JCI1050
  6. 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)
  7. 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) https://doi.org/10.1093/nar/11.5.1475
  8. Falcone, M. and Sarvetnick, N., Cytokines that regulate autoimmune responses. Curr. Opin. Immunol., 11, 670-676 (1999) https://doi.org/10.1016/S0952-7915(99)00035-7
  9. Gri, G., Savio, D., Trinchieri, G., and Ma, X., Synergistic regulation of the human interleukin-12 p40 promoter by NF-$\kappa$B and Ets transcription factors in Epstein-Barr virus-transformed B cells and macrophages. J. BioI. Chem., 273, 6431-6438 (1998) https://doi.org/10.1074/jbc.273.11.6431
  10. 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) https://doi.org/10.1007/BF02977019
  11. 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) https://doi.org/10.1016/S0006-2952(02)00982-6
  12. 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) https://doi.org/10.1016/S0165-2478(99)00136-4
  13. 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)
  14. 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) https://doi.org/10.1038/sj.bjp.0704298
  15. Landolfi, R., Mower, R. L., and Steiner, M., Modification of platelet function and arachidonic acid metabolism by bio-flavonoids. Structure-activity relations. Biochem. Pharmacol., 33, 1525-1530 (1984) https://doi.org/10.1016/0006-2952(84)90423-4
  16. 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-$\gamma$ in monocytic cells. J. Exp. Med., 183, 147-157 (1996) https://doi.org/10.1084/jem.183.1.147
  17. Ma, X. and Trinchieri, G., Regulation of interleukin-12 production in antigen-presenting cells. Adv. Immunol., 79, 55-92 (2001) https://doi.org/10.1016/S0065-2776(01)79002-5
  18. 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)
  19. 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-$\kappa$B. J. BioI. Chem., 274, 7674-7680 (1999) https://doi.org/10.1074/jbc.274.12.7674
  20. Ong, K. C. and Khoo, H. E., Effects of myricetin on glycernia and glycogen metabolism in diabetic rats. Life Sci., 67,1695-1705 (2000) https://doi.org/10.1016/S0024-3205(00)00758-X
  21. Panina-Bordignon, P, Mazzeo, D., Lucia, P. D., D'Ambrosio, D., Lang, R., Fabbri, L., Self, C., and Sinigaglia, F., ${\beta}_2$-Agonists prevent Th1 development by selective inhibition of interleukin 12. J. Clin.lnvest., 100, 1513-1519 (1997) https://doi.org/10.1172/JCI119674
  22. 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) https://doi.org/10.1002/1521-2254(200007/08)2:4<222::AID-JGM117>3.0.CO;2-P
  23. Ross, J. A. and Kasum, C. M., Dietary flavonoids: bioavailability, metabolic effects, and safety. Annu. Rev. Nutr., 22, 19-33 (2002) https://doi.org/10.1146/annurev.nutr.22.111401.144957
  24. 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)
  25. Tsai, S. H., Liang, Y. C., Lin-Shiau, S. Y, and Lin, J. K., Suppression of TNFalpha-mediated NF$\kappa$B activity by myricetin and other flavonoids through down regulating the activity of IKK in ECV304 cells. J. Cell Biochem., 74, 606-615 (1999) https://doi.org/10.1002/(SICI)1097-4644(19990915)74:4<606::AID-JCB10>3.0.CO;2-W