Toxicological Research

Korean Society of Toxicology & Korea Environmental Mutagen Society (한국독성학회)
권호 표지
DOI QR코드

DOI QR Code

Inhibition of the Induction of Nitric Oxide Synthase by Kobusin

  • Published : 2007.06.30
Download PDF
⟨ Previous Next ⟩

Abstract

We isolated a lignan, kobusin from Geranium thunbergii and studied its effect on the expression of inducible nitric oxide synthase (iNOS) gene in a monocyte/macrophage cell line, RAW264.7 cells. Kobusin inhibited lipopolysaccharide (LPS)-stimulated NO production and the expression of iNOS in a concentration-dependent manner. To identify the mechanistic basis for its inhibition of iNOS induction, we examined the effect of kobusin on both the luciferase reporter activity using $NF-{\kappa}B$ minimal promoter and the nuclear translocation of p65. Kobusin suppressed the reporter gene activity and the LPS-induced movement of p65 in to nucleus. $NF-{\kappa}B$ activation is controlled by the phosphorylation and subsequent degradation of $I-{\kappa}B{\alpha}$, and in the present study, we found that $I-{\kappa}B{\alpha}$ phosphorylation was also inhibited by kobusin. Our findings indicate that kobusin may provide a developmental basis for an agent against inflammatory diseases.

Keywords

References

  1. Gilmore, T.D. (1999). The Rel/NF-kappaB signal transduction pathway: introduction. Oncogene, 18, 6842-6844 https://doi.org/10.1038/sj.onc.1203237
  2. Guha, M. and Mackman, N. (2001). LPS induction of gene expression in human monocytes. Cellular Signaling, 13, 85-94 https://doi.org/10.1016/S0898-6568(00)00149-2
  3. Huang, W.C., Chen, J.J. and Chen, C.C. (2003). c-Srcdependent tyrosine phosphorylation of IKKbeta is involved in tumor necrosis factor-alpha-induced intercellular adhesion molecule-1 expression. Journal of Biological Chemistry, 278, 9944-9952 https://doi.org/10.1074/jbc.M208521200
  4. Karin, M. and Ben-Neriah, Y. (2000). Phosphorylation meets ubiquitination: the control of NF-kappaB activity. Annual Review of Immunology, 18, 621-663 https://doi.org/10.1146/annurev.immunol.18.1.621
  5. Kristof, A.S., Goldberg, P., Laubach, V. and Hussain, S.N. (1998). Role of inducible nitric oxide synthase in endotoxin- induced acute lung injury. American Journal of Respiratory & Critical Care Medicine, 158, 1883-1889 https://doi.org/10.1164/ajrccm.158.6.9802100
  6. Liu, Q.H., Jeong, J.E., Choi, E.J., Moon, Y.H. and Woo, E.R. (2006). A new furofuran lignan from Geranium thunbergii Sieb. et Zucc. Archives of Pharmacal Research, 29, 1109-1113 https://doi.org/10.1007/BF02969300
  7. Muller, J.M., Ziegler-Heitbrock, H.W. and Baeuerle, P.A. (1993). Nuclear factor kappa B, a mediator of lipopolysaccharide effects. Immunobiology, 187, 233-256 https://doi.org/10.1016/S0171-2985(11)80342-6
  8. Okuda, T., Yoshida, T. and Mori, K. (1975). Consitutents of Geranium thunbergii Sieb. et Zucc. II. Ellagitannins. Journal of Pharmaceutical Society of Japan (Yakugaku Zasshi), 95, 1462-1466 https://doi.org/10.1248/yakushi1947.95.12_1462
  9. Rojas, S., Acevedo, L., Macias, M., Toscano, R.A., Bye, R., Timmermann, B. and Mata, R. (2003). Calmodulin inhibitors from Leucophyllum ambiguum. Journal of Natural Products, 66, 221-224 https://doi.org/10.1021/np020346i
  10. Strunk, V., Hahnenkamp, K., Schneuing, M., Fischer, L.G. and Rich, G.F. (2001). Selective iNOS inhibition prevents hypotension in septic rats while preserving endotheliumdependent vasodilation. Anestheis & Analgesia, 92, 681- 687 https://doi.org/10.1213/00000539-200103000-00025
  11. Szabo, C. (1998). Role of nitric oxide in endotoxic shock. An overview of recent advances. Annals of the New York Academy of Sciences, 851, 422-425 https://doi.org/10.1111/j.1749-6632.1998.tb09019.x
  12. Trushin, S.A., Pennington, K.N., Carmona, E.M., Asin, S., Savoy, D.N., Billadeau, D.D. and Paya, C.V. (2003). Protein kinase Calpha (PKCalpha) acts upstream of PKCtheta to activate IkappaB kinase and NF-kappaB in T lymphocytes. Molecular & Cellular Biology, 23, 7068-7081 https://doi.org/10.1128/MCB.23.19.7068-7081.2003
  13. Wang, T., Zhang, X. and Li, J.J. (2002). The role of NF-kappaB in the regulation of cell stress responses. International Immunopharmacology, 2, 1509-1520 https://doi.org/10.1016/S1567-5769(02)00058-9
  14. Woo, E.R., Lee, J.Y., Cho, I.J., Kim, S.G. and Kang, K.W. (2005). Amentoflavone inhibits the induction of nitric oxide synthase by inhibiting NF-kappaB activation in macrophages. Pharmacological Research, 51, 539-546 https://doi.org/10.1016/j.phrs.2005.02.002