Archives of Pharmacal Research

, Volume 30, Issue 10, pp 1318–1327 | Cite as

Anti-inflammatory mechanisms of apigenin: inhibition of cyclooxygenase-2 expression, adhesion of monocytes to human umbilical vein endothelial cells, and expression of cellular adhesion molecules

  • Je-Hyuk Lee
  • Hong Yu Zhou
  • So Yean Cho
  • Yeong Shik Kim
  • Yong Soo Lee
  • Choon Sik Jeong
Article

Abstract

The aim of this study was to clarify the anti-inflammatory mechanism of apigenin. Apigenin inhibited the collagenase activity involved in rheumatoid arthritis (RA) and suppressed lipopolysaccharide (LPS)-induced nitric oxide (NO) production in a dose dependent manner in RAW 264.7 macrophage cells. Pretreatment with apigenin also attenuated LPS-induced cyclooxygenase-2 (COX-2) expression. In addition, apigenin profoundly reduced the tumor necrosis factor-a (TNF-a)-induced adhesion of monocytes to HUVEC monolayer. Apigenin significantly suppressed the TNF-a-stimulated upregulation of vascular cellular adhesion mole-cule-1 (VCAM-1)-, intracellular adhesion molecule-1 (ICAM-1)-, and E-selectin-mRNA to the basal levels. Taken together, these results suggest that apigenin has significant anti-inflammatory activity that involves blocking NO-mediated COX-2 expression and monocyte adherence. These results further suggest that apigenin may be useful for therapeutic management of inflammatory diseases.

Key words

Apigenin Collagenase Hyaluronidase Nitric oxide COX-2 Adhesion VCAM-1 ICAM-1 E-selectin 

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. Afanas’ev, I. B., Dorozhko, A. I., Brodskii, A. V, Kostyuk, A. V, and Potapovich, A. I., Chelating and free radical scavenging mechanisms of inhibitory action of rutin and quercetin in lipid peroxidation.Biochem. Pharmacol., 38, 1763–1769 (1989).PubMedCrossRefGoogle Scholar
  2. Ahn, S. M., Yoon, H. Y, Lee, B. G, Park, K. C, Chung, J. H., Moon, C. H., and Lee, S. H., Fructose-1,6-diphosphate attenuates prostaglandin E2 production and Cyclo-oxigenase-2 expression in UVB-irradiated HaCaT keratinocytes.Br. J. Pharmacol., 137, 497–503 (2002).PubMedCrossRefGoogle Scholar
  3. Aigner, T. and Stöve, J., Collagens- major component of the physiological cartilage matrix, major target of cartilage degeneration, major tool in cartilage repair.Adv. Drug Deliv. Rev., 55, 1569–1593 (2003).PubMedCrossRefGoogle Scholar
  4. Amarowicz, R., Troszynska, A., and Shahidi, F., Antioxidant activity of armond seed extract and its fractions.J. Food Lipids, 12, 344–358 (2005).CrossRefGoogle Scholar
  5. Amrani, Y, Chen, H., and Panettieri, R., Activation of tumor necrosis factor receptor 1 in airway smooth muscle: A potential pathway that modulates bronchial hyper-responsiveness in asthma?Respir. Res., 1, 49–53 (2000).PubMedCrossRefGoogle Scholar
  6. Antonella, S., Mario, S., Maria, L., Daniela, M., Francesco, B., and Francesco, C, Flavonoids as antioxidant agents: importance of their interaction with biomembrane.Free Rad. Biol. Med., 19, 481–486 (1995).CrossRefGoogle Scholar
  7. Arts, I. C. W. and Hollenberg, P. C. H., Polyphenols and disease risk in epidemiologic studies.Am. J. Clin. Nutr, 81, 317S- 325S (2005).PubMedGoogle Scholar
  8. Baumann, J., Bruchhausen, F. V, and Wurm, G., Flavonoids and related compounds as inhibitors of arachidonic acid peroxidation.Prostaglandins, 20, 627–639 (1980).PubMedCrossRefGoogle Scholar
  9. Belmont, H. M., Levartovsky, D., Goel, A., Amin, A., Giorno, R., Rediske, J., Skovron, M. L., and Abramson, S. B., Increased nitric oxide production accompanied by the up-regulation of inducible nitric oxide synthase in vascular endothelium from patients with systemic lupus erythematosus.Arthritis Rheum., 40, 1810–1816 (1997).PubMedCrossRefGoogle Scholar
  10. Broide, D. H., Lotz, M., Cuomo, A. J., Coburn, D. A., Federman, E. C, and Wasserman, S. I., Cytokines in symptomatic asthma airway.J. Allergy Clin. Immunol., 89, 958–967 (1992).PubMedCrossRefGoogle Scholar
  11. Chattopadhyay, S., Bhaumik, S., Purkayastha, M., Basu, S., Chaudhuri, A. N., and Gupta, S. D., Apoptosis and necrosis in developing brain cells due to arsenic toxicity and protection with antioxidants.Toxicol. Lett., 136, 65–76 (2002).PubMedCrossRefGoogle Scholar
  12. Choi, J. S., Choi, Y. J., Park, S. H., Kang, J. S., and Kang, Y H., Flavones migrate tumor necrosis factor-a-induced adhesion molecule upregulation in cultured human endothelial cells: role of nuclear factor-KB.J. Nutr., 134, 1013–1019 (2004).PubMedGoogle Scholar
  13. Chun, K. S., Cha, H. H., Shin, J. W., Na, H. K., Park, K. K., Chung, W. Y, and Surh Y J., Nitric oxide induces expression of cyclooxygenase-2 in mouse skin through activation of NFkB.Carcinogenesis, 25, 445–445 (2004)PubMedCrossRefGoogle Scholar
  14. Corpe, C. P., Lee, J. H., Kwon, O., Eck, P., Narayanan, J., Kirk, K. L., and Levine, M., 6-Bromo-6-deoxy-L-ascorbic acid: an ascorbate analog specific for Na+-dependent vitamin C transporter but not glucose transporter pathways.J. Biol. Chem., 280, 5211–5220 (2005).PubMedCrossRefGoogle Scholar
  15. Crofford, L. J., COX-1 and COX-2 tissue expression: Implication and predictions.J. Rheumatol., 24, 15–19 (1997).Google Scholar
  16. Dawson, T. M. and Dawson, V. L, Nitric oxide: actions and pathological roles.Neuroscientist, 1, 7–18 (1995).CrossRefGoogle Scholar
  17. Dubois, R. N., Abramson, S. B., Crofford, L, Gupta, R. A., Simon, L. S., Van De Putte, L. B., and Lipsky, P. E., Cyclo-oxygenase in biology and disease.FASEB J., 12, 1063–1073 (1998).PubMedGoogle Scholar
  18. Edelstam, G A., Laurent, U. B., Lundkvist, O. E., Fraser, J. R., and Laurent, T. C, Concentration and turnover of intraperitoneal hyaluronan during inflammation.Inflammation, 16, 459–469 (1992).PubMedCrossRefGoogle Scholar
  19. Elliott, M. J. and Kandaswami, C, The impact of plant flavonoids on mammalian biology: implications for immunity, inflammation and cancer. In Harborne, J. B. (Eds.). The Flavonoids: Advances in Research Since 1986. Chapman and Hall, London, pp. 619–651, (1986).Google Scholar
  20. Fischer, S. M. and Adam, L. M., Suppression of tumor promoter-induced chemiluminescence in mouse epidermal cells by several inhibitors of arachidonic acid metabolism.Cancer Res., 45, 3130–3136 (1985).PubMedGoogle Scholar
  21. Fisher, N. D. L. and Hollenberg, N. K., Flavonoids for vascular health: the science behind the sweetness.J. Hypertens., 23, 1453–1459 (2005).PubMedCrossRefGoogle Scholar
  22. Goldenberg, M. M., Celecoxib, a selective cyclooxygenase-2 inhibitor for the treatment of rheumatoid arthritis and osteoarthritis.Clin. Ther, 21, 1497–1513(1999).PubMedCrossRefGoogle Scholar
  23. Gupta, S., Farrukh, A., and Hasan, M., Selective growth inhibitory, cell-cycle deregulatory and apoptotic response of apigenin in normal versus human prostate carcinoma cells.Biochem. Biophys. Res. Commun., 287, 914–920 (2001).PubMedCrossRefGoogle Scholar
  24. Hirano, T., Oka, K., and Akiba, M., Anti-proliferative effects of synthetic and naturally occurring flavonoids on tumor cells of the human breast-carcinoma cell line, ZR-75-1. Res.Commun. Chem. Pathol. Pharmacol., 64, 69–78 (1989).Google Scholar
  25. Honda, S., Migita, K., Hirai, Y, Ueki, Y, Yamasaki, S., Urayama, S., Kawabe, Y, Fukuda, T., Kawakami, A., Kamachi, M., Kita, M., Ida, H., Aoyagi, T., and Eguchi, K., Induction of COX-2 expression by nitric oxide in rheumatoid synovial cells.Biochem. Biophysic. Res. Commun., 268, 928–931 (2000).CrossRefGoogle Scholar
  26. Huang, M. T., Lysz, T., Ferraro, T., Abidi, T. F, Laskin, J. D., and Conney, A. N., Inhibitory effects of curcumin onin vitro lipooxygenase and cyclooxygenase activities in mouse epidermis.Cancer Res., 51, 813–819 (1991).PubMedGoogle Scholar
  27. Johansson, N., Saarialho-Kere, U., Airola, K., Herva, R., Nissinen, L, Westermarck, J., Vuorio, E., Heino, J., and Kähäri, V.-M., Collagenase-3 (MMP-3) is expressed by hypertrophic chondrocytes, periostreal cells, and osteoblasts during human fetal bone development.Dev. Dyn., 208, 387–397 (1997).PubMedCrossRefGoogle Scholar
  28. Joyeux, M., Lobstein, A., Anton, R., and Mortier, F, Comparative anti-lipoperoxidant; antinecotic and scavenging properties of terpenes and biflavones from Ginkgo and some flavonoids.Planta Med., 61, 126–129 (1995).PubMedCrossRefGoogle Scholar
  29. Kato, R., Nakadate, T., Yamamoto, S., and Sugimura, T., Inhibition of 12-O-tetradecacanolyphorbol 13-acetate-induced tumor promotion and ornithine decarboxylase activity by quercetin: possible involvement of lipoxugenesis inhibition.Carcino- genesis, 4, 1301–1305 (1983).CrossRefGoogle Scholar
  30. Kelm, M. A., Nair, M. G, Strasburg, G M., and De Witt, D. I., Antioxidant and cyclooxygenase inhibitory phenolic compounds fromOcimum sanctum.Linn. Phytomedicine, 7, 7–13 (2000).Google Scholar
  31. Koskinen, P. K. and Lemstrom, K. B., Adhesion molecule P- selectin and vascular cell adhesion molecule-1 in enhanced heart allograft arteriosclerosis in the rat.Circulation, 95, 191- 196 (1997).PubMedGoogle Scholar
  32. Lee, C. W., Lin, W. N., Lin, C. C, Luo, S. F., Wang, J. S., Pouyssegur, J., and Yang, C. M., Transcriptional regulation of VCAM-1 expression by tumor necrosis factor-α in human tracheal smooth muscle cells: involvement of MAPKs, NF- kB, p300, and histone acetylation.J. Cell. Physiol., 207, 174- 186 (2006).PubMedCrossRefGoogle Scholar
  33. Lee, J., Lee, S. H., Min, K. R., Lee, K. S., Ro, J. S., Ryu, J. C, and Kim, Y, Inhibitory effects of hydrolysable tannins on Ca2-activated HAase.Planta. Med., 59, 381–382 (1993).PubMedCrossRefGoogle Scholar
  34. Lee, S. H., Soyoola, E., Chanmugam, P., Hart, S., Sun, W., Zhong, H., Liou, S., Simmons, D., and Hwang, D., Selective expression of mitogen-inducible cyclooxygenase in macrophages stimulated with lipopolysaccharide.J. Biol. Chem., 267, 25934–25938 (1992).PubMedGoogle Scholar
  35. Lee, Y M., Choi, S. I., Lee, J. W., Jung, S. M., Park, S. M., and Heo, T. R., Isolation of hyaluronidase inhibitory component from the roots ofAstraglus membranaceus Bunge (Astragali Radix).Food Sci. Biotechnol., 14, 263–267 (2005).Google Scholar
  36. Lepley, D. M. and Pelling, J. C, Induction of p21/WAF1 and G1 cell cycle arrest by the chemopreventive agent apigenin.Mol. Carcinog., 19, 74–82 (1997).PubMedCrossRefGoogle Scholar
  37. Liao, X., Lui, J. M., Du, L., Tang, A., Shang, Y, Wang, S. Q., Chen, L. Y, and Chen, Q., Nitric oxide signaling in stretchinduced apoptosis of neonatal rat cardiomyocytes.FASEB J., 20, E1196-E1204 (2006).CrossRefGoogle Scholar
  38. Lin, J. K., Chen, Y C, Huang, Y T., and Lin-Shiau, S. Y, Suppression of protein kinase C and nuclear oncogene expression as possible molecular mechanisms of cancer chemoprevention by apigenin and curcumin.J. Cell. Biochem. Suppl., 28–29, 39–48 (1997).PubMedCrossRefGoogle Scholar
  39. Ludwig, A., Lorenz, M., Grimbo, N., Steinle, F., Meiners, S., Bartsch, C, Stangl, K., Baumann, G, and Stangl, V., The tea flavonoid epigallocatechin-3-gallate reduces cytokine-induced VCAM-1 expression and monocyte adhesion to endothelia cells.Biochem. Biophys. Res. Commun., 316, 659–665 (2004).PubMedCrossRefGoogle Scholar
  40. Maksimowicz-McKinnon, K., Bhatt, D. L., and Calabrese, L. H., Recent advances in vascular inflammation: C-reactive protein and other inflammatory biomarkers.Curr. Opin. Rheumatol., 16, 18–24 (2004).PubMedCrossRefGoogle Scholar
  41. Maruta, A., Ishei, T, and Uyeta, M., Mutagenicity of quercetin and kaempferol on cultured mammarian cells.Gann., 70, 273–276 (1982).Google Scholar
  42. Mayer, K., Merfels, M., Muhly-Reinholz, M., Gokorsch, S., Rosseau, S., Lohmeyer, J., Schwarzer, N., Krüll, M., Suttorp, N., Grimminger, F., and Seeger, W., w-3 Fatty acids suppress monocyte adhesion to human endothelial cells: role of endothelial RAF generation.Am. J. Physiol. Heart Circ. Physiol., 283, H811-H818 (2002).PubMedGoogle Scholar
  43. McPhail, D. B., Hartley, R. C, Gardner, P. T, and Duthie, G G, Kinetic and stoichiometric assessment of the antioxidant activity of flavonoids by electron spin resonance spectroscopy.J. Agric. Food Chem., 51, 1684–1690 (2003).PubMedCrossRefGoogle Scholar
  44. Moosmann, B. and Behl, C, The antioxidant neuroprotective effects of estrogens and phenolic compounds are independent from their estrogenic properties.Biochemistry, 96, 8867- 8872 (1999).Google Scholar
  45. Morel, I., Lescoat, G, Cogrel, P., Sergent, O., Pasdeloup, N., Brissot, P., Cillard, P., and Cillard, J., Antioxidants and ironchelating activities of the flavonoids catechin, quercetin and diosmetin on iron-loaded rat hepatocyte culture.Biochem. Pharmacol., 45, 13–19 (1993).PubMedCrossRefGoogle Scholar
  46. Nielsen, S. E., Young, J. F, Daneshvar, B., Lauridsen, S. T, Knuthsen, P. S., Strom, B., and Dragster, L. O., Effect of parsley (pertroselinum crispum) intake on urinary apigenin excretion blood antioxidant enzymes and bio-makers for oxidative stress in human subjects.Br. J. Nutr., 81, 425–426 (1999).Google Scholar
  47. Noble, P. W., Mackee, C. M., Coweman, M., and Shin, H. S., Hyaluronan fragments activate an NF-kappa B/l-kappa B alpha autoregulatory loop in murine macrophages.J. Exp. Med, 183, 2373–2378 (1996).PubMedCrossRefGoogle Scholar
  48. Nuutila, A. M., Puupponen-Pimiä, R., Aarni, M., and Oksman-Caldentey, K.-M., Comparison of antioxidant activities of onion and garlic extracts by inhibition of lipid peroxidation and radical scavenging activity.Food Chem., 81, 485–493 (2003).CrossRefGoogle Scholar
  49. Oyaizu, M., Studies on product of browning reaction: antioxidative activities of products of browning reaction prepared from glucosamine.Jpn. J. Nutr., 44, 307–315 (1986).Google Scholar
  50. Park, H,, Sin, B. Y, and Kim, H. P., Inhibition of collagenase by anti-inflammatory synthetic flavones.J. Appl. Pharmacol., 14, 36–39 (2006).Google Scholar
  51. Park, S.-H., Park, J. H. Y, Kang, J. S., and Kang, Y H., Involvement of transcription factors in plasma HDL protection against TNF-a-induced vascular cell adhesion molecule-1 expression.Int. J. Biochem. Cell Biol., 35, 168–182 (2003).PubMedCrossRefGoogle Scholar
  52. Psotovâ, J., Chlopèiková, Š., Miketová, P., Hrbáè, J., and Šimánek, V, Chemoprotective effect of plant phenolics against anthracycline-induced toxicity on rat cardiomyocytes. Part III. Apigenin, bacalein, kaempferol, leuteolin and quercetin.Phytother. Res., 18, 516–521 (2004).PubMedCrossRefGoogle Scholar
  53. Rairigh, R. L, Le Cras, T. D., Ivy, D. D., Kinsella, J. P., Richter, G, Horan, M. P., Fan, I. D., and Abman, S. H., Role of inducible nitric oxide synthase in regulation of pulmonary vascular tone in the late gestation ovine fetus.J. Clin. Invest, 101, 15–21 (1998).PubMedCrossRefGoogle Scholar
  54. Safari, M. R. and Sheikh, N., Effects of flavonoids on the susceptibility of low-density lipoprotein to oxidative modification.Prostaglandin Leukot Essent Fatty Acids, 69, 73–77 (2003).CrossRefGoogle Scholar
  55. Sawabe, Y, Nakagomi, K., Iwagami, S., Suzuki, S., and Nakazawa, H., Inhibitory effects of pectic substances on activated hyaluronidase and histamine release from mast cells.Biochim. Biophys. Acta, 1137, 274–278 (1992).PubMedCrossRefGoogle Scholar
  56. Sawabe, Y, Yamasaki, K., Iwagami, S., Kazimura, K., and Nakagommi, K., Inhibitory effects of natural medicines on the enzymes related to the skin.Yakugaku Zasshi, 118, 423–429 (1998).PubMedGoogle Scholar
  57. Schauss, A. G, Merkel, D. J., Glaza, S. M., and Sorenson, S. R., Acute and subchronic oral toxicity studies in rats of a hydrolyzed chicken sternal cartilage preparation.Food Chem. Toxicol., 45, 315–321 (2007).PubMedCrossRefGoogle Scholar
  58. Silverman, M. D., Zamora, D. O., Pan, Y, Texeira, P. V, Planck, S. R., and Rosenbaum, J.T., Cell adhesion molecule expression in cultured human iris endothelial cells.Invest. Ophthalmol. Vis. Sci., 42, 2861–2866 (2001).PubMedGoogle Scholar
  59. Sin, B. Y and Kim, H. P., Inhibition of collagenase by naturallyoccurring flavonoids.Arch. Pharm. Res., 28, 1152–1155 (2005).PubMedCrossRefGoogle Scholar
  60. Singh, J. P., Selvendiran, K., Banu, M. S., Padmavathi, R., and Sakthisekaran, D., Protective role of apigenin on the status of lipid peroxidation and antioxidant defense against hepatocarcinogenesis in Wistar albino rats.Phytomedicine, 11, 309- 314 (2004).PubMedCrossRefGoogle Scholar
  61. Stenman, M., Ainola, M., Valmu, L, Bjartell, A., Ma, G, Stenman, U. H., Sorsa, T., Luukkainen, R., and Konttinen, Y T., Trypsin-2 degrades human type II collagen and is expressed and activated in mesemchymally transformed rheumatoid arthritis synovitis tussue.Am. J. Pathol., 167, 1119–1124 (2005).PubMedGoogle Scholar
  62. Stoewsand, G S., Anderson, J. L., Boyd, J. N., Hrazdina, G, Babish, J. G, Walsh, K. M., and Losco, P., Quercetin: a mutagen, not a carcinogen, in Fisher rats.J. Toxicol. Environ. Hlth., 14, 105–114 (1984).CrossRefGoogle Scholar
  63. Tchetina, E. V., Kobayashi, M., Yasuda, T., Meigers, T., Pidoux, I., and Roole, A. R., Chondrocyte hypertrophy can be induced by a cryptic sequence of type II collagen and is accompanied by in induction of MMP-13 and collagenase activity: implication for development and arthritis.Matrix Biol., 26, 247–258 (2007).PubMedCrossRefGoogle Scholar
  64. Van Acker, S. A., van den Berg, D. J., Tramp, M. N., Griffioen, D. H., van Bennekom, W. P., van der Vijgh, W. J., and Bast, A., Structural aspects of antioxidant activity of flavonoids.Free Rad Biol. Med, 20, 331–342 (1996).PubMedCrossRefGoogle Scholar
  65. Van Dross, R. T., Hong, X., and Pelling, J. C, Inhibition of TPA- induced cyclooxygenase-2 (COX-2) expression by apigenin through downregulation of Akt signal transduction in human keratinocytes.Mol. Carcinog., 44, 83–91 (2005).PubMedCrossRefGoogle Scholar
  66. Vita, J. A., Polyphenols and cardiovascular disease: effects on endothelial and platelet function.Am. J. Clin. Nutr., 81, 292S- 297S (2005).PubMedGoogle Scholar
  67. Waddington, E., Puddey, I. B., and Croft, K. D., Red wine poly- phenolic compounds inhibit atherosclerosis in apolipoprotein E-deficient mice independent of effects on lipid peroxidation.Am. J. Clin. Nutr, 79, 54–61 (2004).PubMedGoogle Scholar
  68. Wei, H., Tye, L., Bresnick, E., and Birt, D. F., Inhibitory effect of apigenin, a plant flavonoid, an epidermal ornithine decarb- oxylase and skin-tumor promotion in mice.Cancer Res., 50, 499–502 (1990).PubMedGoogle Scholar
  69. Xie, W. L, Chipman, J. G, Robertson, D. L, Erikson, R. L., and Simmons, D. L., Expression of a mitogen-responsive gene encoding prostaglandin synthase is regulated by mRNA splicing.Proc. Natl. Acad. Sci. U.S.A., 88, 2692–2696 (1991).PubMedCrossRefGoogle Scholar
  70. Yen, G-C. and Chen, H.-Y, Antioxidant activity of various tea extracts in relation to their antimutagenicity.J. Agric. Food Chem., 43, 27–32 (1995).CrossRefGoogle Scholar
  71. Yukiko, H., Shunjiro, O., and Shozo, F., The correlation between active oxygens scavenging and antioxidative effects of flavonoid.Free Rad. Biol. Med., 16, 845–850 (1994).CrossRefGoogle Scholar
  72. Zimmerman, G A., Mclntyre, T. M., and Prescott, S. M., Adhesion and signaling in vascular cell-cell interactions.J. Clin. Invest, 100, S3-S5 (1997).PubMedGoogle Scholar

Copyright information

© The Pharmaceutical Society of Korea 2007

Authors and Affiliations

  • Je-Hyuk Lee
    • 1
  • Hong Yu Zhou
    • 2
  • So Yean Cho
    • 2
  • Yeong Shik Kim
    • 2
  • Yong Soo Lee
    • 3
  • Choon Sik Jeong
    • 3
  1. 1.Plant Resources Research InstituteDuksung Women’s UniversitySeoulKorea
  2. 2.National Products Research Institute, College of PharmacySeoul National UniversitySeoulKorea
  3. 3.College of PharmacyDuksung Women’s UniversitySeoulKorea

Personalised recommendations