Molecules and Cells

Korean Society for Molecular and Cellular Biology (한국분자세포생물학회)
권호 표지

Methanol Extracts of Stewartia koreana Inhibit Cyclooxygenase-2 (COX-2) and Inducible Nitric Oxide Synthase (iNOS) Gene Expression by Blocking NF-κB Transactivation in LPS-activated RAW 264.7 Cells

  • Lee, Tae Hoon (Graduate School of Biotechnology and Institute of Life Sciences and Resources, Kyung Hee University) ;
  • Kwak, Han Bok (Department of Cell and Developmental Biology, Seoul National University School of Dentistry) ;
  • Kim, Hong-Hee (Department of Cell and Developmental Biology, Seoul National University School of Dentistry) ;
  • Lee, Zang Hee (Department of Cell and Developmental Biology, Seoul National University School of Dentistry) ;
  • Chung, Dae Kyun (Graduate School of Biotechnology and Institute of Life Sciences and Resources, Kyung Hee University) ;
  • Baek, Nam-In (Graduate School of Biotechnology and Institute of Life Sciences and Resources, Kyung Hee University) ;
  • Kim, Jiyoung (Graduate School of Biotechnology and Institute of Life Sciences and Resources, Kyung Hee University)
  • Received : 2007.01.13
  • Accepted : 2007.04.03
  • Published : 2007.06.30
⟨ Previous Next ⟩

Abstract

Cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) are involved in various pathophysiological processes such as inflammation and carcinogenesis. In a search for inhibitors of COX-2 and iNOS production we found that extracts of Stewartia koreana strongly inhibited NO and $PGE_2$ production in LPS-treated macrophage RAW 264.7 cells. We have now shown that the mRNA and protein levels of iNOS and COX-2 are reduced by the Stewartia koreana extract (SKE). SKE inhibited expression of an NF-${\kappa}B$ reporter gene in response to LPS, and gel mobility shift assays revealed that SKE reduced NF-${\kappa}B$ DNA-binding activity. The extract also inhibited LPS-induced phosphorylation of $I{\kappa}B-{\alpha}$ and nuclear translocation of p65. Administration of the extract reduced the symptoms of arthritis in a collagen-induced arthritic mouse model. These results indicate that Stewartia extracts contain potentially useful agents for preventing and treating inflammatory diseases.

Keywords

Acknowledgement

Supported by : Rural Development Administration

References

  1. Ahmad, N., Chen, L. C., Gordon, M. A., Laskin, J. D., and Laskin, D. L. (2002) Regulation of cyclooxygenase-2 by nitric oxide in activated hepatic macrophages during acute endotoxemia. J. Leukoc. Biol. 71, 1005-1011
  2. Amin, A. R., Attur, M., and Abramson, S. B. (1999) Nitric oxide synthase and cyclooxygenases: distribution, regulation, and intervention in arthritis. Curr. Opin. Rheumatol. 11, 202-209 https://doi.org/10.1097/00002281-199905000-00009
  3. Calixto, J. B., Campos, M. M., Otuki, M. F., and Santos, A. R. (2004) Anti-inflammatory compounds of plant origin. Part II. modulation of pro-inflammatory cytokines, chemokines and adhesion molecules. Planta Med. 70, 93-103 https://doi.org/10.1055/s-2004-815483
  4. Choi, Y. H., Han, S. S., Lee, H. O., and Baek, S. H. (2005) Biological activity of bioactive components from Acer ginnala max. Bull. Korean Chem. Soc. 26, 1450-1452 https://doi.org/10.5012/bkcs.2005.26.9.1450
  5. Chung, H. S., Kang, M., Cho, C., Park, S., Kim, H., et al. (2005) Inhibition of lipopolysaccharide and interferon-gamma-induced expression of inducible nitric oxide synthase and tumor necrosis factor-alpha by Lithospermi radix in mouse peritoneal macrophages. J. Ethnopharmacol. 102, 412-417 https://doi.org/10.1016/j.jep.2005.06.028
  6. Dubois, R. N., Abramson, S. B., Crofford, L., Gupta, R. A., Simon, L. S., et al. (1998) Cyclooxygenase in biology and disease. FASEB J. 12, 1063-1073 https://doi.org/10.1096/fasebj.12.12.1063
  7. Geller, D. A., Nussler, A. K., Silvio, M. D., Lowenstein, C. J., Shapiro, R. A., et al. (1993) Cytokines, endotoxin, and glucocorticoids regulate the expression of inducible nitric oxide synthase in hepatocytes. Proc. Natl. Acad. Sci. USA 90, 522-526
  8. Grabley, S. and Thiericke, R. (1999) Bioactive agents from natural sources: trends in discovery and application. Adv. Biochem. Eng. Biothechol. 64, 101-154
  9. Han, S. S., Lo, S. C., Choi, Y., Kim, J. H., and Baek, S. H. (2003) Antioxidant activity of crude extract and pure compounds of acer ginnala Max. Bull. Korean Chem. Soc. 25, 389-391
  10. Kim, J. Y., Kim, D. Y., Lee, Y. S., Lee, B. K., Lee, K. H., et al. (2006) DA-9601, Artemisia asiatica herbal extract, ameliorates airway inflammation of allergic asthma in mice. Mol. Cells 22, 104-112
  11. Kim, R. G., Shin, K. M., Kim, Y. K., Jeong, H. J., Ha, J., et al. (2003) Inhibitin of methanol extract from the aetial parts of saururus chinensis on lipopolysaccharide-induced nitric oxide and prostagladine E2 production from murine macrophage RAW 264.7 Cells. Biol. Pharm. Bull. 26, 481-486 https://doi.org/10.1248/bpb.26.481
  12. Kim, Y., Min, H. Y., Park, H. J., Lee, E. J., Park, E. J., et al. (2004) Supressive effects of nitric oxide production and inducible nitric oxide synthase (iNOS) gene expression by Calystegia soldanella methanol extract on lipopolysaccharideactivated RAW 264.7 cells. Eur. J. Cancer Prev. 13, 419-424 https://doi.org/10.1097/00008469-200410000-00010
  13. Latham, K. A., Whittington, K. B., Zhou, R., Qian, Z., and Rosloniec, E. F. (2005) Ex vivo characterization of the autoimmune T cell response in the HLA-DR1 mouse model of collagen-induced arthritis reveals long-term activation of type II collagen-specific cells and their presence in arthritic joints. J. Immunol. 174, 3978-3985 https://doi.org/10.4049/jimmunol.174.7.3978
  14. Lawrence, T., Gilroy, D. W., Colville-Nash, P. R., and Willoughby, D. A. (2001) Possible new role for NF-kappaB in the resolution of inflammation. Nat. Med. 12, 1291-1297
  15. Lee, J. H., Hwang, B. Y., Kim, K. S., Nam, J. B., Hong, Y. S., et al. (2003) Supression of RelA/p65 transactivation activity by a lignoid manassantin isolated from Saururus chinesis. Biochem. Pharmacol. 66, 1925-1933 https://doi.org/10.1016/S0006-2952(03)00553-7
  16. Lee, S. J., Bai, S. K., Lee, K. S., Namkoong, S., Na, H. J., et al. (2003) Astaxanthin inhibits nitric oxide production and inflammatory gene expression by supression I$\kappa$B kinase-dependent NF-$\kappa$ B activation. Mol. Cells 16, 97-105
  17. Li, Q. and Verma, I. M. (2002) NF-kappaB regulation in the immune system. Nat. Rev. Immunol. 2, 725-734 https://doi.org/10.1038/nri910
  18. Makarov, S. S. (2001) NF-kappa B in rheumatoid arthritis: a pivotal regulator of inflammation, hyperplasia, and tissue destruction. Arthritis Res. 3, 200-206 https://doi.org/10.1186/ar300
  19. Min, B. S., Bae, K. H., Kim, Y. H., Miyashiro, H., Hattori, M., et al. (1999) Screening of Korean plants against human immunodeficiency virus type 1 protease. Phytother. Res. 13, 680-682 https://doi.org/10.1002/(SICI)1099-1573(199912)13:8<680::AID-PTR501>3.0.CO;2-H
  20. Moncada, S. (1999) Nitric oxide: discovery and impact on clinical medicine. J. R. Soc. Med. 92, 164-169 https://doi.org/10.1177/014107689909200402
  21. Nathan, C. (1992) Nitric oxide as a secretory product of mammalian cells. FASEB J. 6, 3051-3064 https://doi.org/10.1096/fasebj.6.12.1381691
  22. Neumann, E., Gay, S., and Muller-Ladner, U. (2005) The RANK/RANKL/osteoprotegerin system in rheumatoid arthritis: new insights from animal models. Arthritis Rheum. 52, 2960-2967 https://doi.org/10.1002/art.21361
  23. Romanovsky, A. A., Ivanov, A. I., and Petresen, S. R. (2006) Microsomal prostaglandin E synthase-1, ephrins, and ephrin kinases as suspected therapeutic targets in arthritis. Ann. N. Y. Acad. Sci. 1069, 183-194 https://doi.org/10.1196/annals.1351.016
  24. Seibert, K., Zhang, Y., Leahy, K., Hauser, S., Masferrer, J., et al. (1994) Pharmacological and biochemical demonstration of the role of cyclooxygenase 2 in inflammation and pain. Proc. Natl. Acad. Sci. USA 91, 12013-12017
  25. Son, K. N., Song, I. S., Shin, Y. H., Pai, T. K., Chung, D. K., et al. (2005) Inhibition of NF-IL6 activity by manassantin B, a dilignan isolated from Saururus chinensis, in phorbol myristate acetate-stimulated U937 promonocytic cells. Mol. Cells 20, 105-111
  26. Song, H. J., Min, Y. S., Shin, C. Y., Jeong, J. H., and Sohn, U. D. (2006) Activation of p38 MAPK is involved in endothelin-1- stimulated COX-2 expression in cultured feline esophageal smooth muscle cells. Mol. Cells 22, 44-50
  27. Sunyer, T., Rothe, L., Jiang, X., Osdoby, P., and Collin-Osdoby, P. (1996) Proinflammatory agents, IL-8 and IL-10, upregulate inducible nitric oxide synthase expression and nitric oxide production in avian osteoclast-like cells. J. Cell. Biochem. 60, 469-483 https://doi.org/10.1002/(SICI)1097-4644(19960315)60:4<469::AID-JCB4>3.0.CO;2-Q
  28. Surh, Y. J., Chun, K. S., Cha, H. H., Han, S. S., Keum, Y. S., et al. (2001) Molecular mechanisms underlying chemopreventive activities of anti-inflammatory phytochemicals: downregulation of COX-2 and iNOS through supression of NFkappa B activation. Mutat. Res. 480, 243-268
  29. Tan, B. K. H. and Vanitha, J. (2004) Immunomodulatory and antimicrobial effects of some traditional Chinese medicinal herbs: A review. Curr. Med. Chem. 11, 1423-1430 https://doi.org/10.2174/0929867043365161