Skip to main content
Log in

Production of Cytokine and NO by RAW 264.7 Macrophages and PBMC In Vitro Incubation with Flavonoids

  • Published:
Archives of Pharmacal Research Aims and scope Submit manuscript

Abstract

Flavonoids, a group of low molecular weight phenylbenzopyrones, have various pharmacological properties including antioxidant activity, anticancer, and immunomodulatory effects. In the present study, lipopolysaccharide (LPS) and phorbol 12-myristate 13-acetate/phytohemagglutinin (PMA/PHA) were used as stimulants for RAW 264.7 macrophages and human peripheral blood mononuclear cell (hPBMC), and tumor necrosis factor (TNF)-a and interleukin (IL)-2 productions were measured. In addition, flavonoids were examined for their effects on LPS-induced NO production in RAW 264.7 macrophages. The results showed that all compounds were not strongly cytotoxic at the tested concentrations on hPBMC and RAW 264.7 macrophages. On immunomodulatory properties, catechin, epigallocatechin (EGC), naringenin, and fisetin repressed NO production and TNF-a secretion. Furthermore, catechin, epigallocatechin gallate (EGCG), epicatechin (EC), luteolin, chrysin, quercetin, and galangin increased IL-2 secretion while EGC, apigenin, and fisetin inhibited the secretion. These results indicated that flavonoids have the capacity to modulate the immune response and have a potential anti-inflammatory activity. There was no obvious structure-activity relationship regard to the chemical composition of the flavonoids and their cell biological effects.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Similar content being viewed by others

References

  • Andreakos, E. T., Foxwell, B. M., Brennan, F. M., Maini, R. N., and Feldmann, M., Cytokines and anti-cytokine biologicals in autoimmunity: present and future.Cytokine Growth Factor Rev., 13, 299–313 (2002).

    Article  PubMed  CAS  Google Scholar 

  • Bors, W., Heller, W., Michel, C., and Saran, M., Radical chemistry of flavonoid antioxidants.Adv. Exp. Med. Biol., 264, 165–170 (1990).

    PubMed  CAS  Google Scholar 

  • Chiou, W. F., Sung, Y. J., Liao J. F., Shum A. Y., and Chen C. F., Inhibitory effect of dehydroevodiamine and evodiamine on nitric oxide production in cultured murine macrophages.J. Nat. Prod., 60, 708–711 (1997).

    Article  PubMed  CAS  Google Scholar 

  • Haraoui, B., Pelletier, J. P., Cloutier, J. M., Faure, M. P., and Martel-Pelletier, J., Synovial membrane histology and immunopathology in rheumatoid arthritis and osteoarthritis.In vivo effects of antirheumatic drugs.Arthritis Rheum., 34, 153–163 (1991).

    Article  PubMed  CAS  Google Scholar 

  • lalenti, A., Moncada, S., and Di, R. M., Modulation of acute inflammation by endogenous nitric oxide.Eur. J. Pharmacol., 211, 177–182 (1992).

    Article  Google Scholar 

  • Kobuchi, H., Droy-Lefaix, M. T., Christen, Y., and Packer, L., Ginkgo biloba extract (Egb 761): Inhibitory effect on nitric oxide production in the macrophage cell line RAW 264.7.Biochem. Pharmacol., 53, 897–903 (1997).

    Article  PubMed  CAS  Google Scholar 

  • Kovacs, E., Serum levels of IL-12 and the production of INF-gamma, IL-2 and IL-4 by peripheral blood mononuclear cells (PBMC) in cancer patients treated withViscum album extract.Biomed. & Pharmacother., 54, 305–310 (2000).

    Article  CAS  Google Scholar 

  • Leonard, W., Chapter 21: Type I cytokines and interferon and their receptors. InPaul W. E. (Eds.).Fundamental immunology.Raven Publishers, Philadelphia, U.S.A., pp. 745–747 (1999).

    Google Scholar 

  • Li, O. and Verma, I. M., NF-kappa B regulation in the immune system.Nat. Rev. Immunol., 2, 725–734 (1992).

    Article  CAS  Google Scholar 

  • Middleton Jr., E., Kandaswami, C., and Theoharides, T. C., The effects of plant flavonoids on mammalian cells: implications for inflammation, heart disease, and cancer.Pharmacol. Rev., 52, 673–751 (2001).

    Google Scholar 

  • Mingari, M. C., Gerosa, F., Carra, G., Accolla, R. S., Moretta, A., Zubler, R. H., Waldmann, T. A., and Moretta, L., Human interleukin-2 promotes proliferation of activated B cellsvia surface receptors similar to those of activated T. cells.Nature, 312, 641–643 (1984).

    Article  PubMed  CAS  Google Scholar 

  • Park, Y. C., Rimbach, G., Saliou, C., Valacchi, G., and Packer, L., Activity of monomeric, dimeric, and trimeric flavonoids on NO production, TNF-α secretion, and NF-kB-dependent gene expression in RAW 264.7 macrophages.FEBS Lett., 465, 93–97 (2000).

    Article  PubMed  CAS  Google Scholar 

  • Radford-Smith, G. and Jewell, D. P., Cytokines and inflammatory bowel disease.Baillieres Clin. Gastroenterol., 10, 151–164 (1996).

    Article  PubMed  CAS  Google Scholar 

  • Rice-Evans, C. A., Miller, N. J., Bolwell, P. G., Bramley, P. M., and Pridham, J. P., The relative antioxidant activities of plant-derived polyphonolic flavonoids.Free Radical Res. Commun., 22, 375–383 (1995).

    Article  CAS  Google Scholar 

  • Rimbach, G., Virgili, F., Park, Y. C., and Packer, L., Effect of procyanidins from Pinus maritima on glutathione levels in endothelial cells challenged by 3-morpholinosydnonimine or activated macrophages.Redox Rep., 4, 171–177 (1999).

    Article  PubMed  CAS  Google Scholar 

  • Robak, J. and Gryglewski, R. J., Flavonoids are scavengers of Superoxide anions.Biochem. Pharmacol., 37, 837–841 (1988).

    Article  PubMed  CAS  Google Scholar 

  • Robertson, M. J. and Ritz, J., Biology and clinical relevance of human natural killer cells.Blood, 76, 2421–2438 (1990).

    PubMed  CAS  Google Scholar 

  • Ryu, J. H., Lee, H. J., Jeong, Y. S., Ryu, S. Y., and Han, Y. N., Yomogin, an inhibitor of nitric oxide production in LPS-activated macrophages.Arch. Pharm. Res., 21, 481–484 (1998).

    Article  PubMed  CAS  Google Scholar 

  • Sandoval, M., Charbonnet, R. M., Okuhama, N. N., Roberts, J., Krenova, Z., Trentacosti, A. M., and Miller, M. J., Cat’s claw inhibits TNFalpha production and scavenges free radicals: role in cytoprotection.Free Radical Biol. Med., 29, 71–78 (2000).

    Article  CAS  Google Scholar 

  • Stichtenoth, D. O. and Frolich, J. C., Nitric oxide and inflammatory joint diseases.Br. J. Rheumatol., 37, 246–247 (1998).

    Article  PubMed  CAS  Google Scholar 

  • Waldmann, T. A., Goldman, C. K., Robb, R. J., Depper, J. M., Leonard, W. J., Sharrow, S. O., Bongiovanni, K. F., Korsmeyer, S. J., and Greene, W. C., Expression of interleukin 2 receptors on activated human B cells.J. Exp. Med., 160, 1450–1466 (1984).

    Article  PubMed  CAS  Google Scholar 

  • Williams, G., Brown, T., Becker, L., Prager, M., and Giroir, B. P., Cytokine-induced expression of nitric oxide synthase in C2C12 skeletal muscle myocytes.Am. J. Physiol., 267, R1020–1025 (1994).

    PubMed  CAS  Google Scholar 

  • Wiseman, H., Role of dietary phyto-oestrogens in the protection against cancer and heart disease.Bio. Comp. Food, 24, 795–800 (1996).

    CAS  Google Scholar 

  • Xie, Q. W., Whisnant, R., and Nathan, C., Promoter of the mouse gene encoding calcium-independent nitric oxide synthase confers inducibility by interferon gamma and bacterial lipopolysaccharide.J. Exp. Med., 177, 1779–1784 (1993).

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Won-Bong Park.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Lyu, SY., Park, WB. Production of Cytokine and NO by RAW 264.7 Macrophages and PBMC In Vitro Incubation with Flavonoids. Arch Pharm Res 28, 573–581 (2005). https://doi.org/10.1007/BF02977761

Download citation

  • Received:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF02977761

Key words

Navigation