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Myricetin blocks lipoteichoic acid-induced COX-2 expression in human gingival fibroblasts

Abstract

Periodontitis is an infectious disease caused by microorganisms present in dental bacterial plaque. Lipoteichoic acid (LTA) is a component of the external membrane of Gram-positive bacteria. It causes septic shock. Ingested flavonoids have been reported to directly affect the regulation of cyclooxygenase-2 (COX-2) expression induced by bacterial toxins. In this study, we examined the effects of four flavonoids (luteolin, fisetin, morin and myricetin) on the activation of ERK1/2, p38 and AKT, and on the synthesis of COX-2 in human gingival fibroblasts treated with LTA from Streptococcus sanguinis. We found that luteolin and myricetin blocked AKT and p38 activation and that myricetin blocked LTA-induced COX-2 expression. The results of our study are important for elucidating the mechanism of action of flavonoid regulation of inflammatory responses.

Abbreviations

COX-2:

cyclooxygenase-2

HGF:

human gingival fibroblasts

LTA:

lipoteichoic acid

MAPK:

mitogen-activated protein kinases

PAMPS:

pathogenassociated molecular patterns

SDS:

sodium dodecyl sulfate

TLR:

Toll-like receptors

References

  1. Gutiérrez-Venegas, G. and Cardoso-Jiménez, P. Lipoteichoic acid promotes accumulation of β-catenin via AKT in human gingival fibroblasts. Int. Immunopharmacol. 11 (2011) 1278–1284.

    Article  PubMed  CAS  Google Scholar 

  2. Gutiérrez-Venegas, G., Contreras-Marmolejo, L.A., Román-Alvárez, P. and Barajas-Torres, C. Aggregatibacter actinomicetemcomitans lipopolysaccharide affects human gingival fibroblast cytoskeletal organization. Cell Biol. Int. 32 (2008) 417–426.

    Article  PubMed  CAS  Google Scholar 

  3. Gutiérrez-Venegas, G. and Contreras-Sánchez, A. Luteolin and fisetin inhibit the effects of lipopolysaccharide obtained from Porphyromonas gingivalis in human gingival fibroblasts. Mol. Biol. Rep. 40 (2013) 477–485.

    Article  PubMed  CAS  Google Scholar 

  4. Graves, D. Cytokines that promote periodontal tissue destruction. J. Periodontol. 79 (2008) 1585–1591.

    Article  PubMed  CAS  Google Scholar 

  5. Kinane, D.F. and Bartold, P. Clinical relevance of the host responses of periodontitis. Periodontol 2000 43 (2007) 278–293.

    Article  PubMed  Google Scholar 

  6. Takashiba, S., Takigawa, M., Takahashi, K., Myokai, F., Nishimura F., Chihatra, T., Kurihara, H., Nomura, Y and Murayama, Y. Interleukin-8 is a major neutrophil chemotactic factor derived from cultured human gingival fibroblasts stimulated with interleukin-1 beta or tumor necrosis factor alpha. Infect. Immun. 60 (1992) 5253–5258.

    PubMed Central  PubMed  CAS  Google Scholar 

  7. Hosokawa, Y., Hosokawa, I., Ozaki, K., Nakae, H. and Matsuo, T. Increase of CCL20 expression by human gingival fibroblasts upon stimulation with cytokines and bacterial endotoxin. Clin. Exp. Immunol. 142 (2005) 285–291.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  8. Hosokawa, Y., Hosokawa, I., Ozaki, K., Nakae, H. and Matsuo, T. CXC chemokine ligand 16 in periodontal diseases: expression in diseased tissues and production by cytokine-stimulated human gingival fibroblasts. Clin. Exp. Immunol. 149 (2007) 146–154.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  9. Hosokawa, I., Hosokawa, Y., Ozaki, K., Nakae, H. and Matsuo, T. Adrenomedullin suppresses tumour necrosis factor alpha-induced CXC chemokine ligand 10 production by human gingival fibroblasts. Clin. Exp. Immunol. 152 (2008) 568–575.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  10. Hosokawa, Y., Hosokawa, I., Ozaki, K., Nakae, H. and Matsuo, T. CC chemokine ligand 17 in periodontal diseases: expression in diseased tissues and production by human gingival fibroblasts. J. Periodontal Res. 43 (2008) 471–477.

    Article  PubMed  CAS  Google Scholar 

  11. Hosokawa, Y., Hosokawa, I., Ozaki, K., Nakae, H. and Matsuo, T. Cytokines differentially regulate CXCL10 production by interferon-gammastimulated or tumor necrosis factor-alpha-stimulated human gingival fibroblasts. J. Periodontal Res. 44 (2009) 225–231.

    Article  PubMed  CAS  Google Scholar 

  12. O’Dell, D.S. and Ebersole, J.L. Avidity of antibody responses to Actinobacillus actinomycetemcomitans in periodontitis. Clin. Exp. Immunol. 101 (1995) 295–301.

    Article  PubMed Central  PubMed  Google Scholar 

  13. Fletcher, J.M., Nair, S.P., Ward, J.M., Henderson, B. and Wilson, M. Analysis of the effect of changing envioromental conditions on the expression patterns of exported surface-associated proteins of the oral pathogen Actinobacillus actinomycetemcomitans. Microb. Pathog. 30 (2001) 359–368.

    Article  PubMed  CAS  Google Scholar 

  14. Hajishengallis, G., Sojar, H., Genco, R.J. and DeNardin, E. Intracellular signaling and cytokine induction upon interactions of Porphyromonas gingivalis fimbriae with pattern-recognition receptors. Immunol. Invest. 33 (2004) 157–172.

    Article  PubMed  CAS  Google Scholar 

  15. Tietze, K., Dalpke, A., Morath, S., Mutters, R., Heeg, K. and Nonnenmacher, C. Differences in innate immune responses upon stimulation with Grampositive and Gram-negative bacteria. J. Periodontal Res. 41 (2006) 447–454.

    Article  PubMed  CAS  Google Scholar 

  16. Hurttia, H.M., Pelto, L.M. and Leino, L. Evidence of an association between functional abnormalities and defective diacylglycerol kinase activity in peripheral blood neutrophils fromo patients with localized juvenile periodontitis. J. Periodontal Res. 32 (1997) 401–407.

    Article  PubMed  CAS  Google Scholar 

  17. Milward, M.R., Chapple, I.L., Wright, H.J., Millard, J.L., Matthews, J.B. and Cooper, P.R. Differential activation of NF-kappaB and gene expression in oral epithelial cells by periodontal pathogens. Clin. Exp. Immunol. 148 (2007) 307–324.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  18. Yamaguchi, T., Naruishi, K., Arai, H., Nishimura, F. and Takashiba, S. IL-6/sIL-6R enhances cathepsin B and L production via caveolin-1-mediated JNK-AP-1 pathway in human gingival fibroblasts. J. Cell Physiol. 217 (2008) 423–432.

    Article  PubMed  CAS  Google Scholar 

  19. Guan, S.M., Zhang, M., He, J.J. and Wu, J.Z. Mitogen-activated protein kinases and phosphatidylinositol 3-kinase are involved in Prevotella intermedia-induced proinflammatory cytokines expression in human periodontal ligament cells. Biochem. Biophys. Res. Commun. 386 (2009) 471–476.

    Article  PubMed  CAS  Google Scholar 

  20. Arai, Y., Watanabe, S., Kimira, M., Shimoi, K., Mochizuki, R. and Kinae, N. Dietary intakes of flavonols, flacones and isoflavones by Japanese women and the inverse correlation between quercetina intake and plasma LDL colesterol concentration. J. Nutr. 130 (2000) 2243–2250.

    PubMed  CAS  Google Scholar 

  21. Maher, P., Dargusch, R., Ehren, J.L., Okada, S., Sharma, K. and Schubert, D. Fisetin powers methylglyoxal dependent protein glycation and limits the complications of diabetes. PLoS ONE 6 (2011) e21226.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  22. Lee, S.E., Jeong, S.I., Yang, H., Park, C.S., Jin, Y.H. and Park, Y.S. Fisetin induces Nrf2-mediated HO-1 expression through PKC-d and p38 in human umbilical vein endotelial cells. J. Cell Biochem. 112 (2011) 2352–2360.

    Article  PubMed  CAS  Google Scholar 

  23. Khan, N, Asim, M., Afaq, E., Abu Zaid, M. and Mukhatai, H. A novel dietary flavonoid fisetin inhibits androgen receptor signaling and tumor growth in athymic mude mice. Cancer Res. 68 (2008) 8555–8563.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  24. Prasath, G.S. and Subramanian, S.P. Modulatory effects of fisetin a bioflavonoid on hyperglycemia by attenuating the key enzymes of carbohydrate metabolismo in hepatic and renal tissues in streptozotocininduced diabetic rats. Eur. J. Pharmacol. 668 (2011) 492–496.

    Article  PubMed  CAS  Google Scholar 

  25. Maher, P. Modulation of multiple pathways involved in the maintenance of neuronal function during aging by fisetin. Genes Nutr. 4 (2009) 297–307.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  26. Kitagawa, S., Sakamoto, H. and Tano, H. Inhibitory effects of flavonoids on free radical-induced hemolysis and their oxidative effects on hemoglobin a. Chem. Pharm. Bull. 52 (2004) 999–1001.

    Article  PubMed  CAS  Google Scholar 

  27. Wu, T.W, Zeng, L.H. and Wu, K.P. Fung. Morin hydrate is a plant-derived and antioxidant-based hepatoprotector. Life Sci. 53 (1993) PL213–PL218.

    PubMed  CAS  Google Scholar 

  28. Galvez, J., Coelho, G., Crespo, M.E., Cruz, T., Rodriguez-Cabezas, M.E., Concha, A., González, M. and Zarzuelo, A. Intestinal anti-inflammatory activity of morin on chronic experimental colitis in the rat. Aliment Pharmacol. Ther. 15 (2001) 2027–2039.

    Article  PubMed  CAS  Google Scholar 

  29. Lee, K.M., Kang, N.J., Han, J.H., Lee, K.W. and Lee, H.J. Myricetin downregulates phorbol ester-induced cyclooxygenase-2 expression in mouse epidermal cells by blocking activation of nuclear factor kappa B. J. Agric. Food Chem. 55 (2007) 9678–9684.

    Article  PubMed  CAS  Google Scholar 

  30. Lee, K.W., Kang, N.J., Rogozin, E.A., Kim, H.G., Cho, Y.Y., Bode, A.M., Lee, H.J., Surh, Y.J., Bowden, G.T. and Dong, Z. Myricetin is a novel natural inhibitor of neoplastic cell transformation and MEK1. Carcinogenesis 28 (2007) 1918–1927.

    Article  PubMed  CAS  Google Scholar 

  31. Kumamoto, T., Fujii M. and Hou, D.X. Myricetin directly targets JAK1 to inhibit cell transformation. Cancer Lett. 275 (2009) 17–26.

    Article  PubMed  CAS  Google Scholar 

  32. Kumamoto, T., Fujii, M. and Hou, D.X. AKT is a direct target for myricetin to inhibit cell transformation. Mol. Cell Biochem. 332 (2009) 33–41.

    Article  PubMed  CAS  Google Scholar 

  33. Kim, J.E, Kwon, J.Y., Lee, D.E., Kang, N.J., Heo, Y.S., Lee, K.W. and Lee, H.J. MKK4 is a novel target for the inhibition of tumor necrosis factor alpha-induced vascular endothelial growth factor expression by myricetin. Biochem. Pharmacol. 77 (2009) 412–421.

    Article  PubMed  CAS  Google Scholar 

  34. Jung, S.K, Lee, K.W., Byun, S., Kang, N.J., Lim, S.H., Heo, Y.S., Bode, A.M., Bowde, G.T., Lee H.J. and Dong, Z. Myricetin suppresses UVBinduced skin cancer by targeting Fyn. Cancer Res. 68 (2008) 6021–6029.

    Article  PubMed  CAS  Google Scholar 

  35. Qian, L.B., Wang, H.P., Chen, Y., Chen, F.X., Ma, Y.Y., Bruce, I.C. and Xia, Q. Luteolin reduces high glucose-mediated impairment of endotheliumdependent relaxation in rat aorta by reducing oxidative stress. Pharmacol. Res. 61 (2006) 281–287.

    Article  CAS  Google Scholar 

  36. Horinaka, M., Yoshida, T., Shiraishi, T., Nakata, S., Wakada, M., Nakanishi, R., Nishino, H., Matsui, H. and Sakai, T. Luteolin induces apoptosis via death receptor 5 upregulation in human malignant tumor cells. Oncogene 24 (2005) 7180–7189.

    Article  PubMed  CAS  Google Scholar 

  37. Ueda, H., Yamazaki, C. and Yamazaki, M. Inhibitory effect of Perilla leaf extract and luteolin on mouse skin tumor promotion. Biol. Pharm. Bull 26 (2003) 560–563.

    Article  PubMed  CAS  Google Scholar 

  38. Ueda, H., Yamazaki, C. and Yamazaki, M. Luteolin as an anti-inflammatory and anti-allergic constituent of Perilla frutescens. Biol. Pharm. Bull. 25 (2002) 1197–1202.

    Article  PubMed  CAS  Google Scholar 

  39. Ueda, H., Yamazaki, C. and Yamazaki, M. Luteolin as an anti-inflammatory and anti-allergic constituent of Perilla flutescens. Biol. Pharm. Bull. 25 (2002) 1197–11202.

    Article  PubMed  CAS  Google Scholar 

  40. Gutiérrez-Venegas, G., Kawasaki-Cárdenas, P., Arroyo-Cruz, S.R. and Maldonado-Frías, S. Luteolin inhibits lipopolysaccharide actions on human gingival fibroblasts. Eur. J. Pharmacol. 10 (2006) 95–105.

    Article  CAS  Google Scholar 

  41. Chomczynski, P. and Sachii, N. Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-cloroform extraction. Anal. Biochem. 162 (1987) 156–159.

    Article  PubMed  CAS  Google Scholar 

  42. Fort, P., Marty, L., Piechaczyk, M., el Sabrouty, S., Dani, C., Jeanteur, P. and Blanchard, J.M. Various rat adult tissues express only one major mRNA species from the glyceraldhyde-2-phosphatre-dehydrogenase multigenic family. Nucleic Acids Res. 13 (1985) 1431–1442.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  43. Uehara, A., Sugawara, S., Tamai, R. and Takada, H. Contrasting responses of human gingival and colonic epithelial cells to lipopolysaccharides, lipoteichoic acids and peptidoglycans in the presence of soluble CD14. Med. Microbiol. Immunol. 189 (2001) 185–192.

    Article  PubMed  CAS  Google Scholar 

  44. Pöllänen, M.T., Salonen, J.I., Grenier, D. and Uitto, V.J. Epithelial cell response to challenge of bacterial lipoteichoic acids and lipopolysaccharides in vitro. J. Med. Microbiol. 49 (2000) 245–252.

    PubMed  Google Scholar 

  45. Liljeroos, M., Vuolteenaho, R., Morath, S., Hartung, T., Hallman, M. and Ojaniemi, M. Bruton’s tyrosine kinase together with PI 3-kinase are part of Toll-like receptor 2 multiprotein complex and mediate LTA induced Tolllike receptor 2 responses in macrophages. Cell Signal. 19 (2007) 625–633.

    Article  PubMed  CAS  Google Scholar 

  46. Lin, C.H., Kuan, I.H., Wang, C.H., Lee, H.M., Lee, W.S., Sheu, J.R., Hsiao, G., Wu, C.H. and Kuo, H.P. Lipoteichoic acid-induced cyclooxygenase-2 expression requires activations of p44/42 and p38 mitogen-activated protein kinase signal pathways. Eur. J. Pharmacol. 450 (2002) 1–9.

    Article  PubMed  CAS  Google Scholar 

  47. Chiang, L.L., Kuo, C.T., Wang, C.H., Chen, T.F., Ho, Y.S., Kuo, H.P. and Lin, C.H. Involvement of nuclear factor-kappaB in lipoteichoic acid-induced cyclooxygenase-2 expression in RAW 264.7 macrophages. J. Pharm. Pharmacol. 55 (2003) 115–123.

    Article  PubMed  CAS  Google Scholar 

  48. Gutiérrez-Venegas, G., Maldonado-Frías, S., Ontiveros-Granados, A. and Kawasaki-Cárdenas, P. Role of p38 in nitric oxide synthase and cyclooxygenase expression and nitric oxide and PGE2 synthesis in human gingival fibroblasts stimulated with lipopolysaccharides. Life Sci. 77 (2005) 60–73.

    Article  PubMed  CAS  Google Scholar 

  49. Takahama, U., Yamamoto, A., Hirota, S. and Oniki, T. Quercetin-dependent reduction of salivary nitrite to nitric oxide under acidic conditions and interaction between quercetin and ascorbic acid during the reduction. J. Agric. Food Chem. 51 (2003) 6014–6020.

    Article  PubMed  CAS  Google Scholar 

  50. Huang, G.C., Chow, J.M., Shen, S.C., Yang, L.Y., Lin, C.W. and Chen, Y.C. Wogonin but not Nor-wogonin inhibits lipopolysaccharide and lipoteichoic acid-induced iNOS gene expression and NO production in macrophages. Int. Immunopharmacol. 7 (2007) 1054–1063.

    Article  PubMed  CAS  Google Scholar 

  51. Chapekar, M.S., Zaremba, T.G., Kuester, R.K. and Hitchins, V.M. Synergistic induction of tumor necrosis factor alpha by bacterial lipopolysaccharide and lipoteichoic acid in combination with polytetrafluoroethylene particles in a murine macrophage cell line RAW 264.7. J. Biomed. Mater. Res. 31 (1996) 251–256.

    Article  PubMed  CAS  Google Scholar 

  52. Dahle, M.K., Øverland, G., Myhre, A.E., Stuestøl, J.F., Hartung, T., Krohn, C.D., Mathiesen, Ø., Wang, J.E. and Aasen, A.O. The phosphatidylinositol 3-kinase/protein kinase B signaling pathway is activated by lipoteichoic acid and plays a role in Kupffer cell production of interleukin-6 (IL-6) and IL-10. Infect. Immun. 72 (2004) 5704–5711.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  53. Bruserud, Ø., Wendelbo, Ø. and Paulsen, K. Lipoteichoic acid derived from Enterococcus faecalis modulates the functional characteristics of both normal peripheral blood leukocytes and native human acute myelogenous leukemia blasts. Eur. J. Haematol. 73 (2004) 340–350.

    Article  PubMed  CAS  Google Scholar 

  54. Lonchampt, M.O., Auguet, M., Delaflotte, S., Goulin-Schulz, J., Chabrier, P.E. and Braquet, P. Lipoteichoic acid: a new inducer of nitric oxide synthase. J. Cardiovasc. Pharmacol. 1 (1992) 20 Suppl 12, S145–147.

    Article  Google Scholar 

  55. Chang, Y.C., Li, P.C., Chen, B.C., Chang, M.S., Wang, J.L., Chiu, W.T. and Lin, C.H. Lipoteichoic acid-induced nitric oxide synthase expression in RAW 264.7 macrophages is mediated by cyclooxygenase-2, prostaglandin E2, protein kinase A, p38 MAPK and nuclear factor-kappaB pathways. Cell Signal. 18 (2006) 1235–1243.

    Article  PubMed  CAS  Google Scholar 

  56. Gutiérrez-Venegas, G. and Bando-Campos, C.G. The flavonoids luteolin and quercetagetin inhibit lipoteichoic acid actions on H9c2 cardiomyocytes. Int. Immunopharmacol. 10 (2010) 1003–1009.

    Article  PubMed  CAS  Google Scholar 

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Correspondence to Gloria Gutiérrez-Venegas.

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Gutiérrez-Venegas, G., Luna, O.A., Arreguín-Cano, J.A. et al. Myricetin blocks lipoteichoic acid-induced COX-2 expression in human gingival fibroblasts. Cell Mol Biol Lett 19, 126–139 (2014). https://doi.org/10.2478/s11658-014-0186-4

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