The Effect of Linarin on LPS-Induced Cytokine Production and Nitric Oxide Inhibition in Murine Macrophages Cell Line RAW264.7

  • Published : 2002.04.01

Abstract

The herb, Chrysanthemum zawadskii var, latilobum commonly known as Gu-Jul-Cho in Korea, used in traditional medicine to treat pneumonia, bronchitis, cough, common cold, pharyngitis, bladder-related disorders, gastroenteric disorders, and hypertension. Linarin is the main active compound and the biological mechanisms of its activity are unclear. It is believed that effects of this herb may be exerted through the pluripotent effectors of linarin due to its ability to treat a variety of afflictions. In this study, the effects of linarin on the mouse macrophages cell line, RAW 264.7, were investigated. It was found that linarin could activate macrophages by producing cytokines. Monocytes and tissue macrophages produce at least two groups of protein mediators of inflammation, interleukin 1 (IL-1 ) and the tumor necrosis factor (TNF). Recent studies have shown that TNF and IL-1 modulate the inflammatory function of endothelial cells, leukocytes, and fibroblasts. $TNF-{\alpha}$ production by macrophages treated with linarin occured in a dose dependent manner However, IL-1 production was largely unaffected by this natural product. This study demonstrated the ability of linarin to activate macrophages both directly and indirectly. Linarin also affect both cytosine production and nitric oxide inhibition, in addition to the expression of some surface molecules. Nitric oxide (NO), derived from L-argin-ine, is produced by two forms(constitutive and inducible) of nitric oxide synthase (NOS). The NO produced in large amounts by inducible NOS is known to be responsible for the vasodilation and hypotension observed in septic shock. Linarin was found to inhibit NO production in the LPS-activated RAW 264.7 cells. Linarin may be a useful candidate as a new drug for treating endotoxemia and the inflammation accompanied by NO overproduction. The linarin-treated total Iymphocytes exhibited cytotoxicity in a dose dependent manner between $20{\;}{\mu}g/ml{\;}and{\;}40{\;}{\mu}g/ml$. These results suggest that linarin may function through macrophage activation.

Keywords

References

  1. Adams, D. O. and Hamilton, T. A., The cell biology of macrophage activation. Annu. Rev. Immunol., 2, 238-318 (1984)
  2. Charles, A. J., Paul, T., and Mark, W., Immunobiology, The immune system in health and disease, Current Biology Publications, London, UK, pp 300, 1999
  3. Cho, J. Y., Park, J., Yoo, E. S., Baik, K. U., and Park, M. H., Effect of ginseng saponin on tumor necrosis factor-$\alpha$ production and T cell proliferation. Yakhak Hoeji, 43, 296-301 (1998)
  4. Choi, Y. E., Ahn, H., and Ryu, J., Polyacetylenes from Angelica gigas and their Inhibitory activity on nitric oxide synthesis in activated macrophages. Biol. Pharm. Bull., 23, 884-886 (2000) https://doi.org/10.1248/bpb.23.884
  5. Djeu, J. Y., Blanchard, D. K., Richards, A. L., and Friedman, H., Tumor necrosis factor induction by Candida albicans from human natural killer cells and monocytes. J. Immunol., 141, 4047-4052 (1988)
  6. Drysdale, B. E., Agarwal, S., and Shin, H. S., Macrophage mediated tumoricidal and activity: Mechanisms of activation and cytotoxicity. Pro. Allergy, 40, 111-161 (1988)
  7. Faris-Eisner, R., Sherman, M. P., Aeberhard, E., and Chaudhuri, G., Nitricoxideis an important mediator for tumoricidal activity in vivo. Proc. Natl. Acad. Sci., USA. 91, 9407-9411 (1994) https://doi.org/10.1073/pnas.91.20.9407
  8. Gossart, S., Cambon, C., Orfila, C., Seguelas, M., Lepert, L., Rami, J., Carre, P., and Pipy, S., Reactive oxygen intermediates as regulators of TNF- production in rat lung inflammation induced by silica. J. Immunol., 156, 1540-1548 (1996)
  9. Im R. J., Flora media coreana vol. 2. part modern medicine, Agricultural publishing house, Pyoungyang, Korea, pp 186, 1998
  10. James, W. L. and Steven, L. K., The Role of Tumor Necrosis Factor and Interleukin 1 in the Immunoinflammatory Response, Pharma Res., 5, 129-139 (1998)
  11. Kim, Y. M., de Vera, M. E., Watkins, S.C., and Billiar, T. R., Nitric oxide protects cultured rat hepatocytes from tumor necrosis factor-alpha-induced apoptosis by inducing heat shock protein. J. Biol. Chem., 272, 1402-1411 (1997) https://doi.org/10.1074/jbc.272.2.1402
  12. Lee, C. B., Illustrated Flora of Korea, Hyaungmoonsa, Seoul, Korea, pp. 754-755, 1982
  13. Linna Z. and Ian R. T., Activation of a mouse macrophage cell line by acemannan: The major carbohydrate fraction from Aloe vera gel. J. Immunopharmacology, 35,119-128 (1996) https://doi.org/10.1016/S0162-3109(96)00135-X
  14. Lorsbach, R. B., Murphy, W. J., Lowenstein, C. J., Snyder, S. H., and Russel, S. W., Expression of the nitric oxide synthase gene in mouse macrophages activated for tumor cell killing. J. Biol. Chem., 268,1908-1913 (1993)
  15. MacMicking, J. D., Nathan, C., Hom, G., Chartrain, N., Fletcher, D. S., Trumbauer, M., Stevens, K., Xie, G-W., Sokol, K., Hutchinson, N., Chen, H., and Mudgett, J. S., Altered response to bacterial infection and endotoxic shock in mice lacking inducible nitric oxide synthase. Cell, 81, 641-650 (1995) https://doi.org/10.1016/0092-8674(95)90085-3
  16. Moncada, S., Palmer, R. M. J., and Higgs, E. A., Nitric oxide: Physiology, pathophysiology, and pharmacology. Pharmacol. Rev., 43,109-142 (1991)
  17. Moore, F. D., Socher, S. H., and Davis, C., Tumor necrosis factor and endotoxin and cause neutrophil activation through separate pathways. Arch. Surg., 126, 70-73(1991) https://doi.org/10.1001/archsurg.1991.01410250076012
  18. Morrison. D. C., and Ryan. J. L., Bacterial endotoxins and host immune responses. Adv. Immunol., 28, 293-450 (1979)
  19. Noel, R.R., John, L. F., and Gerald, M. P, Manual of Clinical Laboratory Immunology, Herman Friedman, U. S. A, pp 233-235, 1991
  20. Pohlman, T. H., Stanness, K. A., Beatty, P. G., Ochs, H. D., and Harlan, J. M., An endothelial cell surface factor (S) induced in vitro by lipoploysaccharide, interleukine 1 and tumor necrosis factor- increase neutrophil adherence by a CDw18-dependent mechanism. J. lmmunol., 136, 4548-4553 (1986)
  21. Stuehr, D. J., and Nathan, C. F., Nitric oxide, a macrophage product responsible for cytostasis and respiratory inhibition in tumor target cells. J. Exp. Med., 169, 1543-1555 (1989) https://doi.org/10.1084/jem.169.5.1543
  22. Wolfe, T. A., and Dasta, J. F., Use of nitric oxide synthse inhibitors as a novel treatment for septic shock. Ann. Pharmacother. 29, 36-46 (1995)