, Volume 26, Issue 5, pp 233–241 | Cite as

A Green Tea-Derived Polyphenol, Epigallocatechin-3-Gallate, Inhibits IκB Kinase Activation and IL-8 Gene Expression in Respiratory Epithelium

  • Philip C. Chen
  • Derek S. Wheeler
  • Vivek Malhotra
  • Kelli Odoms
  • Alvin G. Denenberg
  • Hector R. Wong


Interleukin-8 (IL-8) is a principle neutrophil chemoattractant and activator in humans. There is interest in developing novel pharmacological inhibitors of IL-8 gene expression as a means for modulating inflammation in disease states such as acute lung injury. Herein we determined the effects of epigallocatechin-3-gallate (EGCG), a green tea-derived polyphenol, on tumor necrosis factor-α (TNF-α)-mediated expression of the IL-8 gene in A549 cells. EGCG inhibited TNF-α-mediated IL-8 gene expression in a dose response manner, as measured by ELISA and Northern blot analysis. This effect appears to primarily involve inhibition of IL-8 transcription because EGCG inhibited TNF-α-mediated activation of the IL-8 promoter in cells transiently transfected with an IL-8 promoter-luciferase reporter plasmid. In addition, EGCG inhibited TNF-α-mediated activation of IκB kinase and subsequent activation of the IκBα/NF-κB pathway. We conclude that EGCG is a potent inhibitor of IL-8 gene expression in vitro. The proximal mechanism of this effect involves, in part, inhibition of IκB kinase activation.

tumor necrosis factor-α nuclear factor-κB inflammation signal transduction IκBα 


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  1. 1.
    Bushman, J. L. 1998. Green tea and cancer in humans: a review of the literature. Nutr. Cancer. 31:151–159.Google Scholar
  2. 2.
    Fujiki, H., M. Suganuma, and S. Okabe. 1996. Japanese green tea as a cancer preventive in humans. Nutr. Rev. 54:S67–S70.Google Scholar
  3. 3.
    Katiyar, S. K. and H. Mukhtar. 1996. Tea consumption and cancer. World Rev. Nutr. Diet. 79:154–184.Google Scholar
  4. 4.
    Yang, C. S. and Z. Y. Wang. 1993. Tea and cancer. J. Natl. Cancer Inst. 85:1038–1049.Google Scholar
  5. 5.
    He, P., Y. Noda, and K. Sugiyama. 2001. Green tea suppresses lipopolysaccharide-induced liver injury in d-galactosamine-sensitized rats. J. Nutr. 131:1560–1567.Google Scholar
  6. 6.
    Kuroda, Y. and Y. Hara. 1999. Antimutagenic and anticarcinogenic activity of tea polyophenols. Mutat. Res. 426:67-97Google Scholar
  7. 7.
    Muramatsu, K., M. Fukuyo, and Y. Hara. 1986. Effect of green tea catechins on plasma cholesterol level in cholesterol-fed rats. J. Nutr. Sci. Vitaminol. 32:613–622.Google Scholar
  8. 8.
    Salah, N., N. J. Miller, G. Paganga, L. Tijburg, G. P. Bolwell, and C. Rice-Evans. 1995. Polyphenolic flavenols as scavengers of aqueous phase radicals and as chain-breaking antioxidants. Arch. Biochem. Biophys. 322:339–346.Google Scholar
  9. 9.
    Wiseman, S. A., D. A. Balentine, and B. Frei. 1997. Antioxidants in tea. Crit. Rev. Food Sci. Nutr. 37:705–718.Google Scholar
  10. 10.
    Ho, C.T., Q. Chen, H. Shi, K. Q. Zhang, and R. T. Rosen. 1992. Anti-oxidative effect of polyphenol extract prepared from various Chinese teas. Prev. Med. 21:570–575.Google Scholar
  11. 11.
    Katiyar, S., R. Agarwal, and G. S. Wood. 1992. Inhibition of 12-O-tetradecanoylphorbol-13-acetate-caused tumor production in 7,12-dimethylbenz(a)anthracene-initiated SENCAR mouse skin by a polyphenolic fraction isolated from green tea. Cancer Res. 52:6890–6897.Google Scholar
  12. 12.
    Yang, T. T. and M. W. Koo. 2000. Inhibitory effect of Chinese green tea on endothelial cell-induced LDL oxidation. Atherosclerosis. 148:67–73.Google Scholar
  13. 13.
    Metz, N., A. Lobstein, Y. Schneider, F. Gosse, R. Schleiffer, R. Anton, and F. Raul. 2000. Suppression of azoxymethane-induced preneoplastic lesions and inhibition of cyclooxygenase-2 activity in the colonic mucosa of rats drinking a crude green tea extract. Nutr. Cancer. 38:60–64.Google Scholar
  14. 14.
    Soriani, M., C. Rice-Evans, and R. M. Tyrrell. 1998. Modulation of the UVA activation of heme oxygenase, collagenase, and cyclooxygenase gene expression by epigallocatechin in human skin cells. FEBS Lett. 439:253–257.Google Scholar
  15. 15.
    Chan, M. M., D. Fong, C. T. Ho, and H. I. Huang. 1997. Inhibition of inducible nitric oxide synthase gene expression and enzyme activity by epigallocatechin gallate, a natural product from green tea. Biochem. Pharmacol. 54:1281–1286.Google Scholar
  16. 16.
    Lin, Y. L. and J. K. Lin. 1997. (-)-Epigallocatechin-3-gallate blocks the induction of nitric oxide synthase by down-regulating, lipopolysaccharide-induced activity of transcription factor nuclear factor-kB. Mol. Pharmacol. 52:465–472.Google Scholar
  17. 17.
    Suganuma, M., E. Sueoka, N. Sueoka, S. Okabe, and H. Fujiki. 2000. Mechanisms of cancer prevention by tea polyphenols base on inhibition of TNF-alpha expression. Biofactors. 13:67–72.Google Scholar
  18. 18.
    Aucamp, J., A. Gaspar, Y. Hara, and Z. Apostolides. 1997. Inhibition of xanthine oxidase by catechins from tea (Camellia sinensis). Anticancer Res. 17:4381–4386.Google Scholar
  19. 19.
    Yang, F., H. S. Oz, S. Barve, W. J. S. de Villiers, C. J. McClain, and G. W. Varilek. 2001. The green tea polyphenol (-)-epigallocatechin-3-gallate blocks nuclear factor kB activation by inhibiting IkB kinase activity in the intestinal epithelial cell line IEC-6. Mol. Pharmacol. 60:528–533.Google Scholar
  20. 20.
    Baldwin, A. S. 1996. The NF-kB and IkB proteins: new discoveries and insights. Annu. Rev. Immunol. 14:649–668.Google Scholar
  21. 21.
    Blackwell, T. S. and J. W. Christman. 1997. The role of nuclear factor-kB in cytokine gene regulation. Am. J. Respir. Cell. Mol.n Biol. 17:3–9.Google Scholar
  22. 22.
    Ghosh, S., M. J. May, and E. B. K oop. 1998. NF-kB and Rel proteins: evolutionarily conserved mediators of immune responses. Annu. Rev. Immunol. 16:225–260.Google Scholar
  23. 23.
    DiDonato, J. A., M. Hayakawa, and D. M. Rothwarf. 1997. A cytokine-responsive IkB kinase that activates the transcription factor NF-kB. Nature. 388:548–554.Google Scholar
  24. 24.
    Karin, M. and Y. Ben-Neriah. 2000. Phosphorylation meets ubiquitination: the control of NF-kB activity. Annu. Rev. Immunol. 18:621–663.Google Scholar
  25. 25.
    Mercurio, F., H. Zhu, and B. W. Murray. 1997. IKK-1 and IKK-2: cytokine-activated IkB kinases essential for NF-kB activation. Science. 278:860–866.Google Scholar
  26. 26.
    Mukaida, N., S. Okamato, Y. Ishikawa, and K. Matsushima K. 1994. Molecular mechanisms of interleukin-8 gene expression. J Leukoc Biol. 56:554-558.Google Scholar
  27. 27.
    Nam, S., D. M. Smith, and Q. P. Dou. 2001. Ester bond-containing tea polyphenols potently inhibit proteosome activity in vitro and in vivo. J. Biol. Chem. 276:13322–13330.Google Scholar
  28. 28.
    Allen, G., I. Menendez, M. Ryan, R. Mazor, J. R. Wispe, M. Fiedler, and H. R. Wong. 2000. Hyperoxia synergistically increases TNF-a-induced interleukin-8 gene expression in A549 cells. Am. J. Physiol. 278:L253–L260.Google Scholar
  29. 29.
    Malhotra, V., T. P. Shanley, J. F. Pittet, W. J. Welch, and H. R. Wong. 2001. Geldanamycin inhibits NF-kB activation and interleukin-8 gene expression in cultured human respiratory epithelium. Am. J. Respir. Cell. Mol. Biol. 25:92–97.Google Scholar
  30. 30.
    Wong, H. R., I. Y. Menendez, M. A. Ryan, A. Denenberg, and J. R. Wispe. 1998. Increased expression of heat shock protein-70 protects human respiratory epithelium against hyperoxia. Am. J. Physiol. 275:L836–L841.Google Scholar
  31. 31.
    Luster, A. D. 1998. Chemotactic cytokines that mediate inflammation. N. Engl. J. Med. 338:436–445.Google Scholar
  32. 32.
    Chollet-Martin, S. B., B. Jourdain, C. Gilbert, C. Elbim, J. Chastre, and M. A. Gougerot-Pocidalo. 1996. Interactions between neutrophils and cytokines in blood and alveolar spaces during ARDS. Am. J. Respir. Crit. Care Med. 154:594–601.Google Scholar
  33. 33.
    Standiford, T. J., S. L. Kunkel, and M. A. Basha. 1990. Interleukin-8 gene expression by a pulmonary epithelial cell line, a model for cytokine networks in the lung. J. Clin. Invest. 86:1945–1953.Google Scholar
  34. 34.
    Steinberg, K. P., J. A. Milberg, T. A. Martin, R. J. Maunder, B. A. Cockrill, and L. D. Hudson. 1994. Evolution of bronchoalveolar cell populations in the adult respiratory distress syndrome. Am. J. Respir. Crit. Care Med. 150:113-122.Google Scholar
  35. 35.
    Donnelly, T. J., Meade P., and M. Jagels. 1994. Cytokine, complement, and endotoxin profiles associated with the development of the adult respiratory distress syndrome after severe injury. Crit. Care Med. 22:768–776.Google Scholar
  36. 36.
    Goodman, R. B., R. M. Strieter, and D. P. Martin. 1996. Inflammatory cytokines in patients with persistence of the acute respirator distress syndrome. Am. J. Respir. Crit. Care Med. 154:602–611.Google Scholar
  37. 37.
    Miller, E. J., A. B. Cohen, and S. Nagao. 1992. Elevated levels of NAP-1/interleukin-8 are present in the airspaces of patients with the adult respiratory distress syndrome and are associated with increased mortality. Am. Rev. Respir. Dis. 146:427–432.Google Scholar
  38. 38.
    Roebuck, K. A. 1999. Regulation of interleukin-8 gene expression. J. Interferon Cytokine Res. 19:429–438.Google Scholar
  39. 39.
    Brasier, A. R., M. Jamaluddin, A. Casola, W. Duan, Q. Shen, and R. P. Garofalo. 1998. A promoter recruitment mechanism for tumor necrosis factor a-induced interleukin-8 transcription in type II pulmonary epithelial cells: dependence on nuclear abundance of Rel A, NF-B1, and c-Rel transcription factors. J. Biol. Chem. 273:3551–3561.Google Scholar
  40. 40.
    Pan, M.-H., S. Lin-Shiau, C. Ho, J. Lin, and J. Lin. 2000. Suppression of lipopolysaccharide-induced nuclear factor-kB activity by theaflavin-3,3'-digallate from black tea and other polyphenols through down-regulation of IkB kinase activity in macrophages. Biochem. Pharmacol. 59:357–367.Google Scholar
  41. 41.
    Holtmann, H., R. Winzen, and P. Holland. 1999. Induction of interleukin-8 synthesis integrates effects on transcription and mRNA degradation from at least three different cytokine-or stress-activated signal transduction pathways. Mol. Cell. Biol. 19:6742–6753.Google Scholar
  42. 42.
    Casola A., R. P. Garofalo, M. Jamaluddin, S. Vlahpoulos, and A. R. Brasier. 2000. Requirement of a novel upstream response element in respiratory syncytial virus-induced IL-8 gene expressionn J. Immunol. 164:5944–5951.Google Scholar
  43. 43.
    Mukhtar, H. and N. Amad. 2000. Tea polyphenols: prevention of cancer and optimizing health. Am. J. Clin. Nutr. 71:1689S–1702S.Google Scholar
  44. 44.
    Mukamal, K. J., M. Maclure, J. E. Muller, J. B. Sherwood, and M. A. Mittleman. 2002. Tea consumption and mortality after acute myocardial infarction. Circulation. 105:2474–2479.Google Scholar

Copyright information

© Plenum Publishing Corporation 2002

Authors and Affiliations

  • Philip C. Chen
    • 1
  • Derek S. Wheeler
    • 1
  • Vivek Malhotra
    • 1
  • Kelli Odoms
    • 1
  • Alvin G. Denenberg
    • 1
  • Hector R. Wong
    • 1
  1. 1.Division of Critical Care MedicineChildren's Hospital Medical Center and Children's Hospital Research FoundationCincinnati

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