Skip to main content
SpringerLink
Log in

Flavonoids Inhibit COX-1 and COX-2 Enzymes and Cytokine/Chemokine Production in Human Whole Blood

  • Published:
Inflammation Aims and scope Submit manuscript

Abstract

Cyclooxygenase 2 (COX-2) and the production of cytokines/chemokines are important targets for the modulation of the inflammatory response. Although a large variety of inhibitors of these pathways have been commercialized, some of those inhibitors present severe side effects, governing the search for new molecules, as alternative anti-inflammatory agents. This study was undertaken to study an hitherto not evaluated group of flavonoids, concerning its capacity to inhibit COX-1 and COX-2 enzymes, as well as to inhibit the production of the cytokines and a chemokine, in a complex matrix involved in the systemic inflammatory process, the blood, aiming the establishment of a structure–activity relationship. The results obtained reveal promising flavonoids for the modulation of the inflammatory process, namely the ones presenting a catechol group in B ring, as some flavonoids were able to simultaneously inhibit the production of inflammatory prostaglandin E2 and pro-inflammatory cytokines.

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

Access this article

Log in via an institution

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

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  1. Feghali C.A., Wright T.M. 1997. Cytokines in acute and chronic inflammation. Frontiers in Bioscience 2d12-26.

  2. Dubois, R.N., S.B. Abramson, L. Crofford, R.A. Gupta, L.S. Simon, et al. 1998. Cyclooxygenase in biology and disease. FASEB Journal 12(12): 1063–1073.

    CAS  PubMed  Google Scholar 

  3. Brooks, P., P. Emery, J.F. Evans, H. Fenner, C.J. Hawkey, et al. 1999. Interpreting the clinical significance of the differential inhibition of cyclooxygenase-1 and cyclooxygenase-2. Rheumatology 38(8): 779–788.

    Article  CAS  PubMed  Google Scholar 

  4. Cerella, C., C. Sobolewski, M. Dicato, and M. Diederich. 2010. Targeting COX-2 expression by natural compounds: a promising alternative strategy to synthetic COX-2 inhibitors for cancer chemoprevention and therapy. Biochemical Pharmacology 80(12): 1801–1815.

    Article  CAS  PubMed  Google Scholar 

  5. Mino, T., E. Sugiyama, H. Taki, A. Kuroda, N. Yamashita, et al. 1998. Interleukin-1 alpha and tumor necrosis factor alpha synergistically stimulate prostaglandin E-2-dependent production of interleukin-11 in rheumatoid synovial fibroblasts. Arthritis and Rheumatism 41(11): 2004–2013.

    Article  CAS  PubMed  Google Scholar 

  6. Kushner, I. 1998. Semantics, inflammation, cytokines and common sense. Cytokine & Growth Factor Reviews 9(3–4): 191–196.

    Article  CAS  Google Scholar 

  7. Charo, I.F., and R.M. Ransohoff. 2006. Mechanisms of disease—the many roles of chemokines and chemokine receptors in inflammation. New England Journal of Medicine 354(6): 610–621.

    Article  CAS  PubMed  Google Scholar 

  8. Adams, D.H., and A.R. Lloyd. 1997. Chemokines: leucocyte recruitment and activation cytokines. Lancet 349(9050): 490–495.

    Article  CAS  PubMed  Google Scholar 

  9. Gottlieb, S. 2001. COX 2 inhibitors may increase risk of heart attack. British Medical Journal 323(7311): 471–471.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  10. Funk, C.D., and G.A. FitzGerald. 2007. COX-2 inhibitors and cardiovascular risk. Journal of Cardiovascular Pharmacology 50(5): 470–479.

    Article  CAS  PubMed  Google Scholar 

  11. Rouzer, C.A., and L.J. Marnett. 2009. Cyclooxygenases: structural and functional insights. Journal of Lipid Research 50: S29–S34.

    Article  PubMed Central  PubMed  Google Scholar 

  12. Fantuzzi, G., and P. Ghezzi. 1993. Glucocorticoids as cytokine inhibitors—role in neuroendocrine control and therapy of inflammatory diseases. Mediators of Inflammation 2(4): 263–270.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  13. Prud’homme, G.J. 2000. Gene therapy of autoimmune diseases with vectors encoding regulatory cytokines or inflammatory cytokine inhibitors. Journal of Gene Medicine 2(4): 222–232.

  14. Firestein, G.S. 2003. Evolving concepts of rheumatoid arthritis. Nature 423(6937): 356–361.

    Article  CAS  PubMed  Google Scholar 

  15. Falcone Ferreyra, M.L., S.P. Rius, and P. Casati. 2012. Flavonoids: biosynthesis, biological functions, and biotechnological applications. Frontiers in plant science 3: 222.

    CAS  PubMed Central  PubMed  Google Scholar 

  16. Brunetti, C., M. Di Ferdinando, A. Fini, S. Pollastri, and M. Tattini. 2013. Flavonoids as antioxidants and developmental regulators: relative significance in plants and humans. International Journal of Molecular Sciences 14(2): 3540–3555.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  17. Gomes, A., E. Fernandes, J.L.F.C. Lima, L. Mira, and M.L. Corvo. 2008. Molecular mechanisms of anti-inflammatory activity mediated by flavonoids. Current Medicinal Chemistry 15(16): 1586–1605.

    Article  CAS  PubMed  Google Scholar 

  18. Gomes, A., D. Couto, A. Alves, I. Dias, M. Freitas, et al. 2012. Trihydroxyflavones with antioxidant and anti-inflammatory efficacy. Biofactors 38(5): 378–386.

    Article  CAS  PubMed  Google Scholar 

  19. Ribeiro, D., M. Freitas, S.M. Tomé, A.M.S. Silva, G. Porto, et al. 2013. Modulation of human neutrophils’ oxidative burst by flavonoids. European Journal of Medicinal Chemistry 67: 280–292.

    Article  CAS  PubMed  Google Scholar 

  20. Ribeiro, D., M. Freitas, S.M. Tome, A.M. Silva, G. Porto, et al. 2014. Inhibition of LOX by flavonoids: a structure-activity relationship study. European Journal of Medicinal Chemistry 72: 137–145.

    Article  CAS  PubMed  Google Scholar 

  21. Laufer S., Luik S. 2010. Different methods for testing potential cyclooxygenase-1 and cyclooxygenase-2 inhibitors. In: Ayoub SS, editor. Cyclooxygenases: Methods and Protocols. Vol. 644. Philadelphia: Springer Science+Business Media, LLC, 91–116.

  22. Laufer, S., C. Greim, S. Luik, S.S. Ayoub, and F. Dehner. 2008. Human whole blood assay for rapid and routine testing of non-steroidal anti-inflammatory drugs (NSAIDs) on cyclo-oxygenase-2 activity. Inflammopharmacology 16(4): 155–161.

    Article  CAS  PubMed  Google Scholar 

  23. Myrianthefs, P., S. Karatzas, K. Venetsanou, E. Grouzi, P. Evagelopoulou, et al. 2003. Seasonal variation in whole blood cytokine production after LPS stimulation in normal individuals. Cytokine 24(6): 286–292.

    Article  CAS  PubMed  Google Scholar 

  24. Windheim, M., C. Lang, M. Peggie, L.A. Plater, and P. Cohen. 2007. Molecular mechanisms involved in the regulation of cytokine production by muramyl dipeptide. Biochemical Journal 404(2): 179–190.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  25. Luong, C., A. Miller, J. Barnett, J. Chow, C. Ramesha, et al. 1996. Flexibility of the NSAID binding site in the structure of human cyclooxygenase-2. Nature Structural Biology 3(11): 927–933.

    Article  CAS  PubMed  Google Scholar 

  26. Kurumbail, R.G., A.M. Stevens, J.K. Gierse, J.J. McDonald, R.A. Stegeman, et al. 1996. Structural basis for selective inhibition of cyclooxygenase-2 by anti-inflammatory agents. Nature 384(6610): 644–648.

    Article  CAS  PubMed  Google Scholar 

  27. Wang, H., M.G. Nair, G.M. Strasburg, A.M. Booren, I. Gray, et al. 2000. Cyclooxygenase active bioflavonoids from Balaton™ tart cherry and their structure activity relationships. Phytomedicine 7(1): 15–19.

    Article  CAS  PubMed  Google Scholar 

  28. Llorens, O., J.J. Perez, A. Palomer, and D. Mauleon. 2002. Differential binding mode of diverse cyclooxygenase inhibitors. Journal of Molecular Graphics & Modelling 20(5): 359–371.

    Article  CAS  Google Scholar 

  29. D’Mello, P., M.K. Gadhwal, U. Joshi, and P. Shetgiri. 2011. Modeling of cox-2 inhibotory activity of flavonoids. International Journal of Pharmacy and Pharmaceutical Sciences 3(4): 33–40.

    Google Scholar 

  30. Hou, D.X., T. Yanagita, T. Uto, S. Masuzaki, and M. Fujii. 2005. Anthocyanidins inhibit cyclooxygenase-2 expression in LPS-evoked macrophages: structure-activity relationship and molecular mechanisms involved. Biochemical Pharmacology 70(3): 417–425.

    Article  CAS  PubMed  Google Scholar 

  31. Feng, L., Y. Xia, G.E. Garcia, D. Hwang, and C.B. Wilson. 1995. Involvement of reactive oxygen intermediates in cyclooxygenase-2 expression induced by interleukin-1, tumor necrosis factor-alpha, and lipopolysaccharide. Journal of Clinical Investigation 95(4): 1669–1675.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  32. Landino, L.M., B.C. Crews, M.D. Timmons, J.D. Morrow, and L.J. Marnett. 1996. Peroxynitrite, the coupling product of nitric oxide and superoxide, activates prostaglandin biosynthesis. Proceedings of the National Academy of Sciences of the United States of America 93(26): 15069–15074.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  33. Baumann, J., F. von Bruchhausen, and G. Wurm. 1980. Flavonoids and related compounds as inhibition of arachidonic acid peroxidation. Prostaglandins 20(4): 627–639.

    Article  CAS  PubMed  Google Scholar 

  34. Landolfi, R., R.L. Mower, and M. Steiner. 1984. Modification of platelet-function and arachidonic-acid metabolism by bioflavonoids—structure activity relations. Biochemical Pharmacology 33(9): 1525–1530.

    Article  CAS  PubMed  Google Scholar 

  35. Kim, H.P., K.H. Son, H.W. Chang, and S.S. Kang. 2004. Anti-inflammatory plant flavonoids and cellular action mechanisms. Journal of Pharmaceutical Sciences 96(3): 229–245.

    Article  CAS  Google Scholar 

  36. Lopez-Posadas, R., I. Ballester, C. Mascaraque, M.D. Suarez, A. Zarzuelo, et al. 2010. Flavonoids exert distinct modulatory actions on cyclooxygenase 2 and NF-kappaB in an intestinal epithelial cell line (IEC18). British Journal of Pharmacology 160(7): 1714–1726.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  37. Liang, Y.C., Y.T. Huang, S.H. Tsai, S.Y. Lin-Shiau, C.F. Chen, et al. 1999. Suppression of inducible cyclooxygenase and inducible nitric oxide synthase by apigenin and related flavonoids in mouse macrophages. Carcinogenesis 20(10): 1945–1952.

    Article  CAS  PubMed  Google Scholar 

  38. Raso, G.M., R. Meli, G. Di Carlo, M. Pacilio, and R. Di Carlo. 2001. Inhibition of inducible nitric oxide synthase and cyclooxygenase-2 expression by flavonoids in macrophage J774A.1. Life sciences 68(8): 921–931.

    Article  CAS  PubMed  Google Scholar 

  39. Vitale, P., S. Tacconelli, M.G. Perrone, P. Malerba, L. Simone, et al. 2013. Synthesis, pharmacological characterization, and docking analysis of a novel family of diarylisoxazoles as highly selective cyclooxygenase-1 (COX-1) inhibitors. Journal of Medicinal Chemistry 56(11): 4277–4299.

    Article  CAS  PubMed  Google Scholar 

  40. Fiorucci, S., R. Meli, M. Bucci, and G. Cirino. 2001. Dual inhibitors of cyclooxygenase and 5-lipoxygenase. A new avenue in anti-inflammatory therapy? Biochemical Pharmacology 62(11): 1433–1438.

    Article  CAS  PubMed  Google Scholar 

  41. Martel-Pelletier, J., D. Lajeunesse, P. Reboul, and J.P. Pelletier. 2003. Therapeutic role of dual inhibitors of 5-LOX and COX, selective and non-selective non-steroidal anti-inflammatory drugs. Annals of the Rheumatic Diseases 62(6): 501–509.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  42. Wright, H.L., R.J. Moots, R.C. Bucknall, and S.W. Edwards. 2010. Neutrophil function in inflammation and inflammatory diseases. Rheumatology 49(9): 1618–1631.

    Article  CAS  PubMed  Google Scholar 

  43. Santangelo, C., R. Vari, B. Scazzocchio, R. Di Benedetto, C. Filesi, et al. 2007. Polyphenols, intracellular signalling and inflammation. Annali dell Istituto superiore di sanita 43(4): 394–405.

  44. Burger, D., J.M. Dayer, G. Palmer, and C. Gabay. 2006. Is IL-I a good therapeutic target in the treatment of arthritis? Best Practice & Research in Clinical Rheumatology 20(5): 879–896.

    Article  CAS  Google Scholar 

  45. Kim, E.Y., and K.D. Moudgil. 2008. Regulation of autoimmune inflammation by pro-inflammatory cytokines. Immunology Letters 120(1–2): 1–5.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  46. Proost, P., C. Dewolfpeeters, R. Conings, G. Opdenakker, A. Billiau, et al. 1993. Identification of a novel granulocyte chemotactic protein (Gcp-2) from human tumor-cells - in vitro and in vivo comparison with natural forms of Grp, Ip-10, and Il-8. Journal of Immunology 150(3): 1000–1010.

    CAS  Google Scholar 

  47. Proost, P., A. Wuyts, and J. VanDamme. 1996. The role of chemokines in inflammation. International Journal of Clinical & Laboratory Research 26(4): 211–223.

    Article  CAS  Google Scholar 

  48. Schnyder-Candrian, S., R.M. Strieter, S.L. Kunkel, and A. Walz. 1995. Interferon-alpha and interferon-gamma down-regulate the production of interleukin-8 and ENA-78 in human monocytes. Journal of Leukocyte Biology 57(6): 929–935.

    CAS  PubMed  Google Scholar 

  49. Comalada, M., I. Ballester, E. Bailon, S. Sierra, J. Xaus, et al. 2006. Inhibition of pro-inflammatory markers in primary bone marrow-derived mouse macrophages by naturally occurring flavonoids: analysis of the structure-activity relationship. Biochemical Pharmacology 72(8): 1010–1021.

    Article  CAS  PubMed  Google Scholar 

  50. Calixto, J.B., M.M. Campos, M.F. Otuki, and A.R.S. Santos. 2004. Anti-inflammatory compounds of plant origin. Part II. Modulation of pro-inflammatory cytokines, chemokines and adhesion molecules. Planta Medica 70(2): 93–103.

    Article  CAS  PubMed  Google Scholar 

  51. Min, Y.D., C.H. Choi, H. Bark, H.Y. Son, H.H. Park, et al. 2007. Quercetin inhibits expression of inflammatory cytokines through attenuation of NF-kappa B and p38 MAPK in HMC-1 human mast cell line. Inflammation Research 56(5): 210–215.

    Article  CAS  PubMed  Google Scholar 

  52. Xagorari, A., A. Papapetropoulos, A. Mauromatis, M. Economou, T. Fotsis, et al. 2001. Luteolin inhibits an endotoxin-stimulated phosphorylation cascade and proinflammatory cytokine production in macrophages. Journal of Pharmacology and Experimental Therapeutics 296(1): 181–187.

    CAS  PubMed  Google Scholar 

  53. Ueda, H., C. Yamazaki, and M. Yamazaki. 2002. Luteolin as an anti-inflammatory and anti-allergic constituent of Perilla frutescens. Biological & Pharmaceutical Bulletin 25(9): 1197–1202.

    Article  CAS  Google Scholar 

  54. Kotanidou, A., A. Xagorari, E. Bagli, P. Kitsanta, T. Fotsis, et al. 2002. Luteolin reduces lipopolysaccharide-induced lethal toxicity and expression of proinflammatory molecules in mice. American Journal of Respiratory and Critical Care Medicine 165(6): 818–823.

    Article  PubMed  Google Scholar 

Download references

Acknowledgments

Daniela Ribeiro and Marisa Freitas acknowledge Fundação para a Ciência e a Tecnologia (FCT) the financial support for the PhD grant (SFRH/BD/72966/2010) and Post-doc grant (SFRH/BPD/76909/2011), respectively, in the ambit of “QREN - POPH - Tipologia 4.1 - Formação Avançada”, co-sponsored by FSE and by national funds of MCTES.

Thanks are also due to Fundação para a Ciência e a Tecnologia (FCT, Portugal), the European Union, QREN, FEDER, COMPETE, for funding the Organic Chemistry Research Unit (QOPNA) (project PEst-C/QUI/UI0062/2013). Thanks are also due to Fundação para a Ciência e a Tecnologia (FCT, Portugal), the European Union, QREN, FEDER, COMPETE, for funding the Organic Chemistry Research Unit (QOPNA) (project PEst-C/QUI/UI0062/2013). Sara Tomé also thanks University of Aveiro and Organic Chemistry Research Unit for her fellowship.

We gratefully acknowledge Graça Porto and the nursing staff of the Centro Hospitalar do Porto - Hospital de Santo António blood bank for the collaboration in the recruitment of blood donors to participate in the study.

Conflict of interest

The authors have declared no conflicts of interest.

Author information

Authors and Affiliations

  1. REQUIMTE, Departamento de Ciências Químicas, Faculdade de Farmácia, Universidade do Porto, Rua Jorge Viterbo Ferreira n 228, 4050-313, Porto, Portugal

    Daniela Ribeiro, Marisa Freitas, José L. F. C. Lima & Eduarda Fernandes

  2. Departamento de Química and QOPNA, Universidade de Aveiro, 3810-193, Aveiro, Portugal

    Sara M. Tomé & Artur M. S. Silva

  3. Institute of Pharmacy, Department of Pharmaceutical and Medicinal Chemistry, Eberhard Karls University of Tübingen, Auf der Morgenstelle 8, 72076, Tübingen, Germany

    Stefan Laufer

Authors
  1. Daniela Ribeiro
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Marisa Freitas
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Sara M. Tomé
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Artur M. S. Silva
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Stefan Laufer
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. José L. F. C. Lima
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Eduarda Fernandes
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Eduarda Fernandes.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Ribeiro, D., Freitas, M., Tomé, S.M. et al. Flavonoids Inhibit COX-1 and COX-2 Enzymes and Cytokine/Chemokine Production in Human Whole Blood. Inflammation 38, 858–870 (2015). https://doi.org/10.1007/s10753-014-9995-x

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10753-014-9995-x

KEY WORDS

Search

Navigation