Toxicological Research

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

DOI QR Code

Inhibition of NF-kB/Rel by Paclitaxel in Mouse Macrophages

  • Lim, Jin-Soo (Department of Thoracic and Cardiovascular Surgery, Chosun University College of Medicine) ;
  • Lee, Seog-Ki (Department of Thoracic and Cardiovascular Surgery, Chosun University College of Medicine) ;
  • Jeon, Young-Jin (Department of Pharmacology, Chosun University College of Medicine)
  • Published : 2007.03.31
Download PDF
⟨ Previous Next ⟩

Abstract

We demonstrate that paclitaxel, an antitumor agent derived from yew tree, inhibits LPS- and $IFN-{\gamma}$-induced NF-kB/Rel activation in RAW 264.7 cells. Previously, paclitaxel ($>10{\mu}M$) has been known to induce iNOS gene expression in macrophages. However, in the previous report we described that the pretreatment of macrophages with low concentration of paclitaxel ($0.1{\mu}M$) for 8 h inhibited LPS-induced iNOS gene expression. Pretreatment of RAW 264.7 cells with paclitaxel significantly inhibited NF-kB/Rel transcriptional activation. Electrophoretic mobility shift assay further confirmed that pretreatment of macrophages with paclitaxel inhibited NF-kB/Rel DNA binding. Taxotere, a semisynthetic analog of paclitaxel, also inhibited LPS- and $IFN-{\gamma}$-induced iNOS gene expression. Collectively, these series of experiments indicate that paclitaxel inhibits iNOS gene expression by blocking NF-kB/Rel activation.

Keywords

References

  1. Blagosklonny, M.V., Schulte, T., Nguyen, P., Trepel, J. and Neckers, L.M. (1996). Taxol-induced apoptosis and phosphorylation of Bcl-2 protein involved c-Raf-1 and represents a novel c-Raf-1 signal transduction pathway. Cancer Res., 56, 1851-1854
  2. Cassidy, P.B., Moos, P.J., Kelly, R.C. and Fitzpatrick, F.A. (2002). Cyclooxygenase-2 induction by paclitaxel, docetaxel, and taxane analogues in human monocytes and murine macrophages: structure-activity relationships and their implications. Clin. Cancer Res., 8, 846-855
  3. Cvetkovic, I., Miljkovic, D., Vuckovic, O., Harhaji, L., Nikolic, Z., Trajkovic, V. and Mostarica Stojkovic, M. (2004). Taxol activates inducible nitric oxide synthase in rat astrocytes: the role of MAP kinases and NF-$\kappa$B. Cell. Mol. Life Sci., 61, 1167-1175 https://doi.org/10.1007/s00018-004-3408-5
  4. Das, K.C. and White, C.W. (1997). Activation of NF-$\kappa$B by antineoplastic agents. J. Biol. Chem., 272, 14914-14920 https://doi.org/10.1074/jbc.272.23.14914
  5. Ding, A.H., Porteu, F., Sanchez, E. and Nathan, C.F. (1990). Shared actions of endotoxin and taxol on TNF receptors and TNF release Science, 248, 370-372 https://doi.org/10.1126/science.1970196
  6. Dunnett, M. (1955). A multiple comparison procedure for comparing several treatments with a control. J. Am. Statistics, Assoc., 50, 1096-1121 https://doi.org/10.2307/2281208
  7. Green, L.C., Wagner, D.A., Glogowski, J., Skipper, P.L., Wishnok, J.S. and Tannenbaum, S.R. (1982). Analysis of nitrate, nitrite, and [15N]nitrate in biological fluids. Anal. Biochem., 126, 131-138 https://doi.org/10.1016/0003-2697(82)90118-X
  8. Hibbs, J.B., Jr., Taintor, R.R. and Vavrin, Z. (1987). Macrophage cytotoxicity: role for L-arginine deiminase and imino nitrogen oxidation to nitrite. Science, 235, 473-476 https://doi.org/10.1126/science.2432665
  9. Jeon, Y.J., Han, S.H., Lee, Y.W., Yea, S.S. and Yang, K.H. (1998). Inhibition of NF-kappa B/Rel nuclear translocation by dexamethasone: mechanism for the inhibition of iNOS gene expression. Biochem. Mol. Biol. Int., 45, 435-441
  10. Jeon, Y.J., Yang, K.H., Pulaski, J.T. and Kaminski, N.E. (1996). Attenuation of inducible nitric oxide synthase gene expression by delta 9-tetrahydrocannabinol is mediated through the inhibition of nuclear factor-kappa B/Rel activation. Mol. Pharmacol., 50, 334-341
  11. Kim, Y.M. and Paik, S. (2005). Induction of expression of inducible nitric oxide synthase by taxol in murine macrophage cells. Biochem. Biophys. Res. Commun., 326, 410- 416 https://doi.org/10.1016/j.bbrc.2004.11.043
  12. Li, M.H., Kang, J.S., Kim, H. and Jeon, Y.J. (2006). Pretreatment of macrophages with paclitaxel inhibits iNOS expression. J. Toxicol. Pub. Health, 22, 103-107
  13. Lowenstein, C.J., Alley, E.W., Raval, P., Snowman, A.M., Snyder, S.H., Russell, S.W. and Murphy, W.J. (1993). Macrophage nitric oxide synthase gene: two upstream regions mediate induction by interferon gamma and lipopolysaccharide. Proc. Natl. Acad. Sci. U.S.A., 90, 9730- 9734
  14. Manthey, C.L., Qureshi, N., Stutz, P.L. and Vogel, S.N. (1993). Lipopolysaccharide antagonists block taxol-induced signaling in murine macrophages. J. Exp. Med., 178, 695-702 https://doi.org/10.1084/jem.178.2.695
  15. Palmer, R.M., Ashton, D.S. and Moncada, S. (1988). Vascular endothelial cells synthesize nitric oxide from L-arginine. Nature, 333, 664-666 https://doi.org/10.1038/333664a0
  16. Perera, P.Y., Qureshi, N. and Vogel, S.N. (1996). Paclitaxel (Taxol)-induced NF-$\kappa$B translocation in murine macrophages. Infect. Immun., 64, 878-884
  17. Rietschel, E.T. and Brade, H. (1992). Bacterial endotoxins. Sci. Am., 267, 54-61
  18. Rowinsky, E.K. (1994). Update on the antitumor activity of paclitaxel in clinical trials. Ann. Pharmacother., 28, S18- S22
  19. Xie, H., Chiles, T.C. and Rothstein, T.L. (1993a). Induction of CREB activity via the surface Ig receptor of B cells. J. Immunol., 151, 880-889
  20. Xie, Q.W., Kashiwabara, Y. and Nathan, C. (1994). Role of transcription factor NF-kappa B/Rel in induction of nitric oxide synthase. J. Biol. Chem., 269, 4705-4708
  21. Xie, Q.W., Qhisnant, R. and Nathan, C. (1993b). Promoter of the mouse gene encoding calcium-independent nitric oxide synthase confers inducibility by interferon-g and bacterial lipopolysaccharide. J. Exp. Med., 177, 1779-1784 https://doi.org/10.1084/jem.177.6.1779