Advertisement

Tumor Biology

, Volume 37, Issue 5, pp 6571–6579 | Cite as

Flavones induce immunomodulatory and anti-inflammatory effects by activating cellular anti-oxidant activity: a structure-activity relationship study

  • Soumaya Kilani-Jaziri
  • Nadia Mustapha
  • Imen Mokdad-Bzeouich
  • Dorra El Gueder
  • Kamel Ghedira
  • Leila Ghedira-Chekir
Original Article

Abstract

Flavonoids impart a variety of biological activities, including anti-oxidant, anti-inflammatory, and anti-genotoxic effects. This study investigated the effects of flavone luteolin and apigenin on immune cell functions, including proliferation, natural killer (NK) cell activity, and cytotoxic T lymphocyte (CTL) activity of isolated murine splenocytes. We report for the first time that flavones enhance lymphocyte proliferation at 10 μM. Luteolin and apigenin significantly promote lipopolysaccharide (LPS)-stimulated splenocyte proliferation and enhance humoral immune responses. Luteolin induces a weak cell proliferation of lectin-stimulated splenic T cells, when compared to apigenin. In addition, both flavones significantly enhance NK cell and CTL activities. Furthermore, our study demonstrated that both flavones could inhibit lysosomal enzyme activity, suggesting a potential anti-inflammatory effect. The anti-inflammatory activity was concomitant with the cellular anti-oxidant effect detected in macrophages, red blood cells, and splenocytes. We conclude from this study that flavones exhibited an immunomodulatory effect which could be ascribed, in part, to its cytoprotective capacity via its anti-oxidant activity.

Keywords

Luteolin Apigenin Immunomodulation Cellular anti-oxidant activity NK activity CTL activity 

Notes

Acknowledgments

The authors wish to acknowledge the Ministry of Higher Education, Scientific Research, and Technology of Tunisia for the financial support of this study.

Compliance with ethical standards

Conflicts of interest

None

References

  1. 1.
    Shukla S, Mehta A, John J, Mehta P, Vyas SP, Shukla S. Immunomodulatory activities of ethanolic extract of Caesalpinia bonducella seeds. J Ethnopharmacol. 2009;125:252–6.CrossRefPubMedGoogle Scholar
  2. 2.
    Cao G, Sofic E, Prior RL. Anti-oxidant and prooxidant behavior of flavonoids: structure-activity relationships. Free Radical Bio Med. 1997;22(5):749–60.CrossRefGoogle Scholar
  3. 3.
    Sanbongi C, Suzuki N, Sakane T. Polyphenols in chocolate, which have anti-oxidant activity, modulate immune functions in humans in vitro. Cell Immunol. 1997;177:129–36.CrossRefPubMedGoogle Scholar
  4. 4.
    Benavente-Garcia O, Castillo J. Update on uses and properties of citrus flavonoids: new findings in anti-cancer, cardiovascular, and anti-inflammatory activity. J Agric Food Chem. 2008;56:6185–205.CrossRefPubMedGoogle Scholar
  5. 5.
    Kilani-Jaziri S, Neffati A, Limem I, Boubaker J, Skandrani I, Ben Sghair M, et al. Relationship correlation of antioxidant and antiproliferative capacity of Cyperus rotundus products towards K562 erythroleukemia cells. Chemico-Biological Interactions. 2009;181(1):14.CrossRefGoogle Scholar
  6. 6.
    Limem I, Harizi H, Ghedira K, Chekir-Ghedira L. Leaf extracts from Phlomis crinita Cav. subs. mauritanica Munby affect immune cell functions in vitro. Immunopharm Immunotoxicol. 2010;33:309–14.CrossRefGoogle Scholar
  7. 7.
    Blasa M, Angelino D, Gennari L, Ninfali P. The cellular antioxidant activity in red blood cells (CAA-RBC): a new approach to bioavailability and synergy of phytochemicals and botanical extracts. Food Chem. 2011;125:685–91.CrossRefGoogle Scholar
  8. 8.
    Mosmann T. Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays. J Immunol Meth. 1983;65:55–63.CrossRefGoogle Scholar
  9. 9.
    Manosroi A, Saraphanchotiwitthaya A, Manosroi J. Immunomodulatory activities of Clausena excavata Burm. f. wood extracts. J Ethnopharmacol. 2003;89:155–60.CrossRefPubMedGoogle Scholar
  10. 10.
    Sarangi I, Ghosh D, Bhutia SK, Mallick SK, Maiti TK. Anti-tumor and immunomodulating effects of Pleurotus ostreatus mycelia-derived proteoglycans. Inter Immunopharmacol. 2006;6:1287–97.CrossRefGoogle Scholar
  11. 11.
    Manosroi A, Saraphanchotiwitthaya A, Manosroi J. In vitro immunomodulatory effect of Pouteria cambodiana (Pierre ex Dubard) Baehni extract. J Ethnopharmacol. 2005;101:90–4.CrossRefPubMedGoogle Scholar
  12. 12.
    Wolfe KL, Liu RH. Cellular anti-oxidant activity (CAA) assay for assessing anti-oxidants, foods, and dietary supplements. J Agric Food Chem. 2007;55:8896–907.CrossRefPubMedGoogle Scholar
  13. 13.
    Liu YZ, Cao YG, Ye JQ, et al. Immunomodulatory effects of pro-anthocyanidin A-1 derived in vitro from Rhododendron spiciferum. Fitoterapia. 2010;81:108–14.CrossRefPubMedGoogle Scholar
  14. 14.
    Halliwell B. Role of free radicals in the neurodegenerative diseases: therapeutic implications for anti-oxidant treatment. Drugs Aging. 2001;18:685–716.CrossRefPubMedGoogle Scholar
  15. 15.
    Wang D, Ma Y, Wang J, et al. Natural killer cells in innate defense against infective pathogens. J Clin Cell Immunol. 2013; S13. doi: 10.4172/2155-9899.S13-006
  16. 16.
    Zhang Y, Song TT, Cunnick JE, Murphy PA, Hendrich S. Daidzein and genistein glucuronides in vitro are weakly estrogenic and activate human natural killer cells at nutritionally relevant concentrations. J Nutr. 1999;129:399–405.PubMedGoogle Scholar
  17. 17.
    Kim MH, Albertsson P, Xue Y, Kitson RP, Nannmark U, Goldfarb RH. Expression of matrix metalloproteinases and their inhibitors by rat NK cells: inhibition of their expression by genistein. In Vivo. 2000;14:557–64.PubMedGoogle Scholar
  18. 18.
    Robertson MJ, Ritz J. Biology and clinical relevance of natural killer cells. Blood. 1990;76:2421–38.PubMedGoogle Scholar
  19. 19.
    Guo TL, McCay JA, Zhang LX, et al. Genistein modulates immune responses and increases host resistance to B16F10 tumor in adult female B6C3F1 mice. J Nutr. 2001;131:3251–8.PubMedGoogle Scholar
  20. 20.
    Kitson RP, Ohashi M, Brunson KW, Goldfarb RH. Flavone acetic acid enhances accumulation of IL-2 activated NK cells within established metastases. In Vivo. 1998;12:593–7.PubMedGoogle Scholar
  21. 21.
    Bhouri W, Boubaker J, Kilani S, Ghedira K, Chekir-Ghedira L. Flavonoids from Rhamnus alaternus L. (Rhamnaceae): kaempferol 3-O-b-isorhamninoside and rhamnocitrin 3-O-B-isorhamninoside protect against DNA damage in human lymphoblastoid cell and enhance anti-oxidant activity. S Afr J Bot. 2012;8057–62.Google Scholar
  22. 22.
    Carevic O, Djokic S. Comparative studies on the effect of erythromycin A and azithromycin upon extracellularly release of lysosomal enzymes in inflammatory process. Agents Actions. 1988;25:124–31.CrossRefPubMedGoogle Scholar
  23. 23.
    Narendhirakannan RT, Subramanian S, Kandaswamy M. Anti-inflammatory and lysosomal stability actions of Cleome gynandra L. studied in adjuvant induced arthritic rats. Food Chem Toxicol. 2007;45:1001–12.CrossRefPubMedGoogle Scholar
  24. 24.
    Havsteen B. Flavonoids, a class of natural products of high pharmacological potency. Biochem Pharmacol. 1983;32:1141–8.CrossRefPubMedGoogle Scholar
  25. 25.
    Hendriks JJ, de Vries HE, van der Pol SM, van den Berg TK, van Tol EA, Dijkstra CD. Flavonoids inhibit myelin phagocytosis by macrophages; a structure-activity relationship study. Biochem Pharmacol. 2003;65:877–85.CrossRefPubMedGoogle Scholar
  26. 26.
    Matsuda H, Morikawa T, Ando S, Toguchida I, Yoshikawa M. Structural requirements of flavonoids for nitric oxide production inhibitory activity and mechanism of action. Bioorg Med Chem. 2003;11:1995–2000.CrossRefPubMedGoogle Scholar
  27. 27.
    Murzakhmetova M, Moldakarimov S, Tancheva L, Abarova S, Serkedjieva J. Antioxidant and prooxidant properties of a polyphenol-rich extract from Geranium sanguineum L. in vitro and in vivo. Phytother Res. 2008;22:746–51.CrossRefPubMedGoogle Scholar
  28. 28.
    Azam S, Hadi N, Khan NU, Hadi SM. Prooxidant property of green tea polyphenols epicatechin and epigallocatechin-3-gallate: implications for anticancer properties. Toxico in Vitro. 2004;18:555–61.CrossRefGoogle Scholar
  29. 29.
    Rice-Evans CA, Miller NJ, Paganga G. Structure–anti-oxidant activity relationships of flavonoids and phenolic acids. Free Radic Biol Med. 1996;20:933–56.CrossRefPubMedGoogle Scholar
  30. 30.
    Galati G, Sabzevari O, Wilson JX, O’Brien PJ. Prooxidant activity and cellular effects of the phenoxyl radicals of dietary flavonoids and other polyphenolics. Toxicol. 2002;177:91–104.CrossRefGoogle Scholar

Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2015

Authors and Affiliations

  • Soumaya Kilani-Jaziri
    • 1
    • 2
  • Nadia Mustapha
    • 1
    • 2
  • Imen Mokdad-Bzeouich
    • 1
    • 2
  • Dorra El Gueder
    • 1
    • 2
  • Kamel Ghedira
    • 2
  • Leila Ghedira-Chekir
    • 1
    • 2
  1. 1.Laboratory of Cellular and Molecular Biology, Faculty of Dental MedicineUniversity of MonastirMonastirTunisia
  2. 2.Unit of Bioactive and Natural Substances and Biotechnology UR12ES12, Faculty of Pharmacy of MonastirUniversity of MonastirMonastirTunisia

Personalised recommendations