Gold Sodium Thiomalate Inhibits iNOS Gene Expression in RAW 264.7 Macrophage: Differential Regulation by Gold Sodium Thiomalate and Sodium Salicylate

Gold Sodium Thiomalate에 의한 유도성 Nitric Oxide Synthase Gene의 발현억제: Gold 제제와 Sodium Salicylate의 차이점

  • 임종호 (을지의과대학교 약리학 교실) ;
  • 배진영 (을지의과대학교 약리학 교실)
  • Published : 2002.12.01

Abstract

Gold sodium thiomalate (GST, gold compound) is a widely used anti-arthritic, anti-rheumatic and anti-inflammatory drug that is considered a good alternative to sodium salicylate (NaSA) for individuals who cannot tolerate salicylates. Nitric oxide (NO) synthesized by inducible nitric oxide synthase (iNOS) has been implicated as a mediator of inflammation. Recent evidence suggests that anti-inflammatory effect of NaSA lies in the inhibition of iNOS, but nothing has been reported about the direct effect of iNOS expression by GST. The present study was designed to elucidate sequentially the action mechanisms of GST and NaSA on lipopolysaccharide (LPS) plus interferon-gamma (IFN-$\gamma$) induced iNOS expression in RAW 264.7 macrophages. Both GST and NaSA inhibited NO production and iNOS protein expression in a dose dependent manner. GST inhibited iNOS mRNA expression induced by LPS plus IFN-$\gamma$, whereas NaSA did not. These findings suggest that GST may exert anti-arthritic, anti-rheumatic and anti-inflammatory effect by inhibiting iNOS expression induced by LPS plus IFN-$\gamma$ at transcriptional level, whereas NaSA exert its effect by inhibiting iNOS expression at the translational or posttranslational level.

Keywords

References

  1. Berg J., Fellier H., Christoph T., Grarup J., and Stimmeder D. 1999). The analgesic NSAID lornoxicam inhibits cyclooxygenase (C0X)-1/-2, inducible nitric oxide synthase (iNOS), and the formation of mterleukin (1L)-6 in vitro. Inflamm. Res., 48(7), 369-79 https://doi.org/10.1007/s000110050474
  2. Chen Y.C., Shen S.C., Lee W.R., Hou W.C., Yang L.L., and Lee T.J. (2001). Inhibition of nitric oxide synthase inhibitors and lipopolysacchaiide induced mducible NOS and cyclooxy-genase-2 gene expressions by rutin, quercetin, and quercetin pentaacetate in RAW 264.7 macrophages. J. Cell. Biochem., 82(4), 537-48 https://doi.org/10.1002/jcb.1184
  3. Dimartino M.J. and Walz D.T. (1997). Inhibition of lysosomal enzyme release from rat leukocytes by auranofin. A new chrysotherapeutic agent, Inflammation, 2(2), 131-42 https://doi.org/10.1007/BF00918675
  4. Finkelslein A.E., Roisman F.R., and Walz D.T. (1997). Effect of auranofin, a new antiarthritic agent, on immune complexinduced release of lysosomal enzymes from human leukocytes. Inflammation, 2(2), 143-50 https://doi.org/10.1007/BF00918676
  5. Friedman H., Specter S., Klein T., Newton C., Rivenbark M., Rowlands D., and Walz D.T. (1990). Auranofin-induced suppression of autoimmume antibody production and inflammation in gcnetically autoimmune-prone mice. Inflammation, 14(4), 463-70 https://doi.org/10.1007/BF00914097
  6. Hirohata S., Nakanishi K., Yanagida T., Kawai M., Kiktichi H., and Isshi K. (1999). Synergistic inhibition of human B cell activation by gold sodium thiomalatc and auranofin. Clin. Immunol., 91(2), 226-33
  7. Honoki K, Muramatsu T., Nakatani C., Iida T., and Shirai T. (1998), A case of nonscaning inflammatory epidermolysis bullosa acquisita: characterization of IgG autoantibodies by immunofluorescence, immunoblotting and immunogold elcctron microscopy. J. Dermtatol., 25(10), 666-72
  8. jacobs A.T. and Ignarro L.J. (2001). Lipopolysaccharide induced expression of interferon-beta mediates the timing of inducible nitric-oxide synthase induction in RAW 264.7 macrophages. J. Biol. Chem., 21;276(51), 47950-7
  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 dexamelhasone: mechaanism for the inhibition of iNOS gene expression. Biochem. Mol. Biol. Int., 45(3), 435-41
  10. Kim T.S., Kang B.Y., Lee M.H., Choe Y.K., and Hwang S.Y. (2001). Inhibition of interleukin-12 production by auranofin, an anti-rheumatic gold compound, deviates CD4(+) T cells from the Th1 to the Th2 pathway. Br J. Pharmacol. Oct,134(3), 571-8 https://doi.org/10.1038/sj.bjp.0704298
  11. Liu J., Akahoshi T., Namai R., Matsui T., and Kondo H. (2000). Effcct of auranofin, an antirheumatic drug, on neutrophil apoptosis. Inflamm. Res., 49(9), 445-51 https://doi.org/10.1007/s000110050615
  12. Nathan C. and Xie Q.W. (1994). Nitric oxide synthase; role tolls, and controls. Cell., 78, 915-918 https://doi.org/10.1016/0092-8674(94)90266-6
  13. Ryu Y.S., Lee J.H., Seok J.H., Hong J.H., Lee Y.S., Lim J.H., Kim Y.M. and Hur G.M. (2000). Acetamiiiophen inhibits iNOS gene expression in RAW 264.7 macrophages: differential regula-tion. of NF-kappaB by acctaminophen and salicylates. Bio-chem. Biophys. Res. Commun., 16;272(3), 758-64 https://doi.org/10.1006/bbrc.2000.2863
  14. Schmidt H.H. and Walter U. (1994). NO at work. Cell., 78, 919-925 https://doi.org/10.1016/0092-8674(94)90267-4
  15. Veihelmann A., Krombach F., Refior HJ.., and Messmer K. (1999). Effects of NO synthase inhibitors on the synovial microcireulation in the mouse knee joint., J. Vasc. Resm., 36(5), 379-84 https://doi.org/10.1159/000025677
  16. Waddington S.N., Moslcy K., and Cattell V. (1999). Induced nitric oxide (NO) synthesis in hetcrologous nephrotoxic nephritis; effects of selective inhibition in neutrophil-dependent glomeruloncpritis. Clin. Exp. Immunolm., 118(2), 309-14
  17. Whan l-Ian J., Gon Lee B., Kee Kim Y., Woo Yoon J., Kyoung Jin H., Hong S., Young Lee H., Ro Lee K., and Woo Lec H. (2001). Ergolide, sesquiterpcne lactone from Inula britannica, inhibits inducible nitric oxide synthase and cyclo-oxygenase 2 expression in RAW 264.7 macrophages through the inactivation of NF-kappaB. Br J. Pharmucol., 133(4), 503-12 https://doi.org/10.1038/sj.bjp.0704099
  18. Yamada R., Sano H., Hla T., Hashiramoto A., Fukui W., Miyazaki S., Kohno M., Tsubouchi Y., Kusaka Y., and Kondo M. (1999). Auranofin inhibits inteileukin-lbeta-induced transcript of cyclooxygenase-2 on cultured human synoviocytes. Eur. J. Pharmacol., 26, 385(1), 71-9 https://doi.org/10.1016/S0014-2999(99)00707-4
  19. Yanni, G., Farahat, M.N.M.R., Poston, R-N. and Panayi, G.S., (1994). Intramuscular gold decreases cytokinc expression and macrophage numbers in the rheumatoid synovial membrane. Ann. Rheum. Dis., 53, 315-322 https://doi.org/10.1136/ard.53.5.315