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Archives of pharmacal research : a publication of the Pharmaceutical Society of Korea v.33 no.6, 2010년, pp.939 - 945   SCIE
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TBK1-Targeted Suppression of TRIF-Dependent Signaling Pathway of Toll-like Receptor 3 by Auranofin

Park, Se-Jeong    (Departments of Medical Science, College of Medical Sciences, Soonchunhyang University   ); Lee, A-Neum    (Departments of Biomedical Laboratory Science, College of Medical Sciences, Soonchunhyang University   ); Youn, Hyung-Sun    (Departments of Medical Science, College of Medical Sciences, Soonchunhyang University  );
  • 초록

    Toll-like receptors (TLRs) play an important role in induction of innate immune responses. The stimulation of TLRs by microbial components triggers two branches of downstream signaling pathways: myeloid differential factor 88 (MyD88)- and toll-interleukin-1 receptor domain-containing adapter inducing interferon- ${\beta}$ (TRIF)-dependent signaling pathways. Auranofin, a sulfur-containing gold compound (Au[I]), has been widely used for the treatment of rheumatoid arthritis. Since dysregulation of TLRs can lead to severe systemic inflammatory and joint destructive process in rheumatoid arthritis, auranofin-mediated modulation of TLR activation may have therapeutic potential against such diseases. Previously, we demonstrated that auranofin suppressed TLR4 signaling pathway by inhibiting TLR4 dimerization induced by LPS. Here, we examined the effect of auranofin on signal transduction via the TRIFdependent pathway induced by a TLR3 agonist. Auranofin inhibited nuclear factor-kB and interferon (IFN) regulatory factor 3 (IRF3) activation induced by polyinosinic-polycytidylic acid (poly[I:C]). Auranofin inhibited poly[I:C]-induced phosphorylation of IRF3 as well as IFNinducible genes such as IFN inducible protein-10. Furthermore, auranofin inhibited TBK1 kinase activity in vitro. All the results suggest that auranofin suppress TLR signaling at multiple steps.


  • 주제어

    Toll-like receptors .   Auranofin .   Poly[I:C] .   TRIF .   TBK1 .   IRF3.  

  • 참고문헌 (24)

    1. Ahn, S. I., Lee, J. K., and Youn, H. S., Inhibition of homodimerization of toll-like receptor 4 by 6-shogaol. Mol. Cells, 27, 211-215 (2009). 
    2. Akira, S., Uematsu, S., and Takeuchi, O., Pathogen recognition and innate immunity. Cell, 124, 783-801 (2006). 
    3. Andreakos, E., Sacre, S., Foxwell, B. M., and Feldmann, M. The toll-like receptor-nuclear factor kappaB pathway in rheumatoid arthritis. Front. Biosci., 10, 2478-2488 (2005). 
    4. Bjorkbacka, H., Fitzgerald, K. A., Huet, F., Li, X., Gregory, J. A., Lee, M. A., Ordija, C. M., Dowley, N. E., Golenbock, D. T., and Freeman, M. W., The induction of macrophage gene expression by LPS predominantly utilizes Myd88- independent signaling cascades. Physiol. Genomics, 19, 319-330 (2004). 
    5. Fitzgerald, K. A., Mcwhirter, S. M., Faia, K. L., Rowe, D. C., Latz, E., Golenbock, D. T., Coyle, A. J., Liao, S. M., and Maniatis, T., IKKepsilon and TBK1 are essential components of the IRF3 signaling pathway. Nat. Immunol., 4, 491-496 (2003). 
    6. Gao, J. J., Filla, M. B., Fultz, M. J., Vogel, S. N., Russell, S. W., and Murphy, W. J., Autocrine/paracrine IFN-alphabeta mediates the lipopolysaccharide-induced activation of transcription factor Stat1alpha in mouse macrophages: pivotal role of Stat1alpha in induction of the inducible nitric oxide synthase gene. J. Immunol., 161, 4803-4810 (1998). 
    7. Honda, K. and Taniguchi, T., IRFs: master regulators of signalling by Toll-like receptors and cytosolic patternrecognition receptors. Nat. Rev. Immunol., 6, 644-658 (2006). 
    8. Jeon, K. I., Jeong, J. Y., and Jue, D. M., Thiol-reactive metal compounds inhibit NF-kappa B activation by blocking I kappa B kinase. J. Immunol., 164, 5981-5989 (2000). 
    9. Jeon, K. I., Byun, M. S., and Jue, D. M., Gold compound auranofin inhibits IkappaB kinase (IKK) by modifying Cys-179 of IKKbeta subunit. Exp. Mol. Med., 35, 61-66 (2003). 
    10. Kawai, T., Takeuchi, O., Fujita, T., Inoue, J., Muhlradt, P. F., Sato, S., Hoshino, K., and Akira, S., Lipopolysaccharide stimulates the MyD88-independent pathway and results in activation of IFN-regulatory factor 3 and the expression of a subset of lipopolysaccharide-inducible genes. J. Immunol., 167, 5887-5894 (2001). 
    11. Lin, R., Heylbroeck, C., Pitha, P. M., and Hiscott, J., Virusdependent phosphorylation of the IRF-3 transcription factor regulates nuclear translocation, transactivation potential, and proteasome-mediated degradation. Mol. Cell. Biol., 18, 2986-2996 (1998). 
    12. Lin, R., Heylbroeck, C., Genin, P., Pitha, P. M., and Hiscott, J., Essential role of interferon regulatory factor 3 in direct activation of RANTES chemokine transcription. Mol. Cell. Biol., 19, 959-966 (1999). 
    13. Navarro, L. and David, M., p38-dependent activation of interferon regulatory factor 3 by lipopolysaccharide. J. Biol. Chem., 274, 35535-35538 (1999). 
    14. Schafer, S. L., Lin, R., Moore, P. A., Hiscott, J., and Pitha, P. M., Regulation of type I interferon gene expression by interferon regulatory factor-3. J. Biol. Chem., 273, 2714-2720 (1998). 
    15. Simon, L. S., DMARDs in the treatment of rheumatoid arthritis: current agents and future developments. Int. J. Clin. Pract., 54, 243-249 (2000). 
    16. Stern, I., Wataha, J. C., Lewis, J. B., Messer, R. L., Lockwood, P. E., and Tseng, W. Y., Anti-rheumatic gold compounds as sublethal modulators of monocytic LPS-induced cytokine secretion. Toxicol. In Vitro, 19, 365-371 (2005). 
    17. Stetson, D. B. and Medzhitov, R., Type I interferons in host defense. Immunity, 25, 373-381 (2006). 
    18. Takeda, K. and Akira, S., Toll-like receptors in innate immunity. Int. Immunol., 17, 1-14 (2005). 
    19. Wietek, C. and O'neill, L. A., Diversity and regulation in the NF-kappaB system. Trends Biochem. Sci., 32, 311-319 (2007). 
    20. Youn, H. S., Lee, J. Y., Saitoh, S. I., Miyake, K., and Hwang, D. H., Auranofin, as an anti-rheumatic gold compound, suppresses LPS-induced homodimerization of TLR4. Biochem. Biophys. Res. Commun., 350, 866-871 (2006a). 
    21. Youn, H. S., Saitoh, S. I., Miyake, K., and Hwang, D. H., Inhibition of homodimerization of Toll-like receptor 4 by curcumin. Biochem. Pharmacol., 72, 62-69 (2006b). 
    22. Youn, H. S., Ahn, S. I., and Lee, B. Y., Guggulsterone suppresses the activation of transcription factor IRF3 induced by TLR3 or TLR4 agonists. Int. Immunopharmacol., 9, 108-112 (2009). 
    23. Medzhitov, R., Preston-Hurlburt, P., and Janeway, C. A., Jr., A human homologue of the Drosophila Toll protein signals activation of adaptive immunity. Nature, 388, 394-397 (1997). 
    24. Yamada, R., Sano, H., Hla, T., Hashiramoto, A., Fukui, W., Miyazaki, S., Kohno, M., Tsubouchi, Y., Kusaka, Y., and Kondo, M., Auranofin inhibits interleukin-1beta-induced transcript of cyclooxygenase-2 on cultured human synoviocytes. Eur. J. Pharmacol., 385, 71-79 (1999). 

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    2. 2009 "Isoliquiritigenin의 toll-like receptor agonists에 의해서 유도된 NF-${\kappa}$B 활성화와 cyclooxygenase-2 발현 억제" 한국식품과학회지 = Korean journal of food science and technology 41 (2): 220~224    
    3. 2009 "Oak Wood Vinegar Suppresses the Expression of Cyclooxygenase-2 Induced by TLR4 Agonist" Journal of experimental & biomedical sciences = 대한의생명과학회지 15 (3): 257~260    
    4. 2010 "Suppression of TRIF-dependent signaling pathway of Toll-like receptors by oak wood vinegar in RAW264.7 macrophages" Molecular & cellular toxicology 6 (1): 73~78    
    5. 2011 "Ovalbumin에 의한 cyclooxygenase-2와 inducible nitric oxide synthase 유도" 한국식품과학회지 = Korean journal of food science and technology 43 (1): 110~113    
    6. 2011 "Suppression of the TRIF-dependent signaling pathway of toll-like receptors by (E)-isopropyl 4-oxo-4-(2-oxopyrrolidin-1-yl)-2-butenoate" BMB reports 44 (7): 468~472    
    7. 2011 "Suppression of cyclooxygenase-2 expression induced by Toll-like receptor 2 or 4 agonists by (E)-isopropyl 4-oxo-4-(2-oxopyrrolidin-1-yl)-2-butenoate" Molecular & cellular toxicology 7 (1): 39~44    
  • 이아늠 (4)

  • Youn, Hyung-Sun (29)

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