T 세포 및 대식세포 기능에 대한 Silybin의 조절효과

Immunomodulatory Effect of Silybin on T Cell- and Macrophage-mediated Functions

  • 조재열 (강원대학교 BT학부대학 생물소재공학)
  • Cho, Jae-Youl (School of Bioscience and Biotechnology, Kangwon National University)
  • 발행 : 2007.08.31

초록

Silybin is known to be a major active flavonoid component isolated from Silybum marianum, a hepatoprotective medicinal plant. In this study, we examined the immunomodulatory role of silybin on T cell and macrophage-mediated immune responses. To do this, the proliferation of splenic lymphocytes and CD8+ CTLL-2 cells under mitogenic stimulation with lipopolysaccharide (LPS), concanavalin (Con) A and interleukin (IL)-2 and the production of $TNF-{\alpha}$ and NO from LPS- and $IFN-{\gamma}$-activated macrophages was evaluated under silybin treatment. The mitogenic proliferation of splenic lymphocytes induced by LPS and Con A was strongly diminished by silybin in a dose-dependent manner. Moreover, the proliferation of CD8+ CTLL-2 cells was also negatively modulated by the compound. In contrast, silybin did not strongly suppress the proliferation of normal splenocytes and T cell line Sup-T1 cells, indicating that the inhibitory effect of silybin may be due to blocking only mitogenic responses of splenic lymphocytes. In addition, silybin inhibited $TNF-{\alpha}$ production in LPS-stimulated RAW264.7 cells. Effect of silybin however was distinct, according to NO-inducing stimuli. Thus, silybin only blocked NO production induced by $IFN-{\gamma}$ but not LPS and the inhibition was increased when PMA was co-treated with $IFN-{\gamma}$. Unlike NO inhibition, however, this compound protected the cytotoxic damage of RAW264.7 cells induced by both LPS and $IFN-{\gamma}$. Therefore, our data suggest that silybin may participate in host immune responses mediated by T cells and macrophages via regulating mitogenic proliferation, and the production of $TNF-{\alpha}$ and NO, depending on cellular stimuli.

키워드

참고문헌

  1. Jaeschke, H. : Role of inflammation in the mechanism of acetaminophen-induced hepatotoxicity. Expert Opin. Drug Metab. Toxicol. 1, 389 (2005) https://doi.org/10.1517/17425255.1.3.389
  2. Schwabe, R. F. and Brenner, D. A. : Mechanisms of liver injury. I. TNF-alpha-induced liver injury: role of IKK, JNK, and ROS pathways. Am. J. Physiol. Gastrointest. Liver Physiol. 290, G583 (2006) https://doi.org/10.1152/ajpgi.00422.2005
  3. Tilg, H., Kaser, A. and Moschen, A. R. : How to modulate inflammatory cytokines in liver diseases. Liver Int. 26, 1029 (2006) https://doi.org/10.1111/j.1478-3231.2006.01339.x
  4. Li, Z. and Diehl, A. M. : Innate immunity in the liver. Curr. Opin. Gastroenterol. 19, 565 (2003) https://doi.org/10.1097/00001574-200311000-00009
  5. Roberts, R. A., Ganey, P. E., Ju, C., Kamendulis, L. M., Rusyn, I. and Klaunig, J. E. : Role of the Kupffer cell in mediating hepatic toxicity and carcinogenesis. Toxicol. Sci. 96, 2 (2007) https://doi.org/10.1093/toxsci/kfl173
  6. Schumann, J., Prockl, J., Kiemer, A. K., Vollmar, A. M., Bang, R. and Tiegs, G. : Silibinin protects mice from T cell-dependent liver injury. J. Hepatol. 39, 333 (2003) https://doi.org/10.1016/S0168-8278(03)00239-3
  7. Gupta, O. P., Sing, S., Bani, S., Sharma, N., Malhotra, S., Gupta, B. D., Banerjee, S. K. and Handa, S. S. : Anti-inflammatory and anti-arthritic activities of silymarin acting through inhibition of 5-lipoxygenase. Phytomedicine. 7, 21 (2000)
  8. Gu, M., Singh, R. P., Dhanalakshmi, S., Agarwal, C. and Agarwal, R. : Silibinin inhibits inflammatory and angiogenic attributes in photocarcinogenesis in SKH-1 hairless mice. Cancer Res. 67, 3483 (2007) https://doi.org/10.1158/0008-5472.CAN-06-3955
  9. Kang, J. S., Jeon, Y. J., Kim, H. M., Han, S. H. and Yang, K. H. : Inhibition of inducible nitric-oxide synthase expression by silymarin in lipopolysaccharide-stimulated macrophages. J. Pharmacol. Exp. Ther. 302, 138 (2002)
  10. Cho, J. Y., Baik, K. U., Jung, J. H. and Park, M. H. : In vitro anti-inflammatory effects of cynaropicrin, a sesquiterpene lactone, from Saussurea lappa. Eur. J. Pharmacol. 398, 399 (2000)
  11. Lee, J. S., Kim, S. G., Kim, H. K., Lee, T. H., Jeong, Y. I., Lee, C. M., Yoon, M. S., Na, Y. J., Sub, D. S., Park, N. C., Choi, I. H., Kim, G. Y., Choi, Y. H., Chung, H. Y. and Park, Y. M. : Silibinin polarizes Th1/Th2 immune responses through the inhibition of immunostimulatory function of dendritic cells. J. Cell Physiol. 210, 385 (2007) https://doi.org/10.1002/jcp.20852
  12. Polyak, S. J., Morishima, C., Shuhart, M. C., Wang, C. C., Liu, Y. and Lee, D. Y. : Inhibition of T-cell inflammatory cytokines, hepatocyte NF-kappaB signaling, and HCV infection by standardized silymarin. Gastroenterology 132, 1925 (2007) https://doi.org/10.1053/j.gastro.2007.02.038
  13. Singh, R. P., Dhanalakshmi, S., Mohan, S., Agarwal, C. and Agarwal, R. : Silibinin inhibits UVB- and epidermal growth factor-induced mitogenic and cell survival signaling involving activator protein-1 and nuclear factor-kappaB in mouse epidermal JB6 cells. Mol. Cancer Ther. 5, 1145 (2006) https://doi.org/10.1158/1535-7163.MCT-05-0478
  14. Beere, H. M. : Death versus survival: functional interaction between the apoptotic and stress-inducible heat shock protein pathways. J. Clin. Invest. 115, 2633 (2005) https://doi.org/10.1172/JCI26471
  15. Kang, J. S., Park, S. K., Yang, K. H. and Kim, H. M. : Silymarin inhibits TNF-alpha-induced expression of adhesion molecules in human umbilical vein endothelial cells. FEBS Lett. 550, 89 (2003) https://doi.org/10.1016/S0014-5793(03)00827-5
  16. Lee, S. K., Kim, H. S., Lee, H. J., Lee, J., Jeon, B. H., Jun, C. D., Lee, S. K. and Kim, E. C. : Dual effect of nitric oxide in immortalized and malignant human oral keratinocytes: induction of apoptosis and differentiation. J. Oral. Pathol. Med. 35, 352 (2006) https://doi.org/10.1111/j.1600-0714.2006.00439.x
  17. Kim, B. H. and Cho, J. Y. : Honokiol-mediated cytoprotective effects. J. Pharm. Pharmacol. Submitted (2007)
  18. Das, S. K. and Vasudevan, D. M. : Protective effects of silymarin, a milk thistle (Silybium marianum) derivative on ethanol-induced oxidative stress in liver. Indian J. Biochem. Biophys. 43, 306 (2006)
  19. Moulisova, V., Srbova, M., Jedlickova, O., Sebestian, J. and Jegorov, A. : Silybin reduces lipid peroxidation of rat hepatocyte membrane caused by cyclosporin A. Biochemistry (Mosc). 71, 1110 (2006) https://doi.org/10.1134/S0006297906100087
  20. Manna, S. K., Mukhopadhyay, A., Van, N. T. and Aggarwal, B. B. : Silymarin suppresses TNF-induced activation of NF-kappa B, c-Jun N-terminal kinase, and apoptosis. J. Immunol. 163, 6800 (1999)
  21. Yoo, H. G., Jung, S. N., Hwang, Y. S., Park, J. S., Kim, M. H., Jeong, M., Ahn, S. J., Ahn, B. W., Shin, B. A., Park, R. K. and Jung, Y. D. : Involvement of NF-kappaB and caspases in silibinin-induced apoptosis of endothelial cells. Int. J. Mol. Med. 13, 81 (2004)
  22. Cho, J. Y., Skubitz, K. M., Katz, D. R. and Chain, B. M. : CD98-dependent homotypic aggregation is associated with translocation of protein kinase Cdelta and activation of mitogen-activated protein kinases. Exp. Cell Res. 286, 1 (2003) https://doi.org/10.1016/S0014-4827(03)00106-X
  23. Varga, Z., Ujhelyi, L., Kiss, A., Balla, J., Czompa, A. and Antus, S. : Effect of silybin on phorbol myristate actetate-induced protein kinase C translocation, NADPH oxidase activity and apoptosis in human neutrophils. Phytomedicine. 11, 206 (2004) https://doi.org/10.1078/0944-7113-00358