Molecular & Cellular Toxicology

The Korean Society of Toxicogenomics and Toxicoproteomics (대한독성유전 단백체학회)
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Suppression of the TRIF-dependent Signaling Pathway of Toll-like Receptor by Cadmium in RAW264.7 Macrophages

  • Park, Se-Jeong (Department of Medical Science, College of Medical Sciences, Soonchunhyang University) ;
  • Youn, Hyung-Sun (Department of Medical Science, College of Medical Sciences, Soonchunhyang University)
  • Published : 2009.09.30
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Abstract

Toll-like receptors (TLRs) play an important role in host defense by sensing invading microbial pathogens. The stimulation of TLRs by microbial components triggers the activation of the myeloid differential factor 88 (MyD88)- and toll-interleukin-1 receptor domain-containing adapter inducing interferon-$\beta$ (TRIF)-dependent downstream signaling pathways. TLR/MyD88 signaling pathway induces the activation of nuclear factor-kappa B (NF-${\kappa}B$) and the expression of inflammatory cytokine genes, including tumor necrosis factor-alpha, interleukin (IL)-6, IL-12, and IL-$1{\beta}$. On the other hand, TLR/TRIF signaling pathway induces the delayed-activation of NF-${\kappa}B$ and interferon regulatory factor 3 (IRF3), and the expression of type I interferons (IFNs) and IFN-inducible genes. The divalent heavy metal cadmium (Cd) is clearly toxic to most mammalian organ systems, especially the immune system. Yet, the underlying toxic mechanism(s) remain unclear. Cd inhibits the MyD88-dependent pathway by ceasing the activity of inhibitor-${\kappa}B$ kinase. However, it is not known whether Cd inhibits the TRIF-dependent pathway. Presently, Cd inhibited NF-${\kappa}B$ and IRF3 activation induced by lipopolysaccharide (LPS) and polyinosinic-polycytidylic acid. Cd inhibited LPS-induced IRF3 phosphorylation and IFN-inducible genes such as interferon inducible protein-10 and regulated on activation normal T-cell expressed and secreted (RANTES). These results suggest that Cd can modulate TRIF-dependent signaling pathways of TLRs.

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References

  1. Medzhitov, R., Preston-Hurlburt, P. & Janeway, C. A., Jr. A human homologue of the Drosophila Toll protein signals activation of adaptive immunity. Nature 388:394-397 (1997) https://doi.org/10.1038/41131
  2. Bjorkbacka, H. et al. The induction of macrophage gene expression by LPS predominantly utilizes Myd88-independent signaling cascades. Physiol Genomics 19:319-330 (2004) https://doi.org/10.1152/physiolgenomics.00128.2004
  3. Takeda, K. & Akira, S. Toll-like receptors in innate immunity. Int Immunol 17:1-14 (2005) https://doi.org/10.1093/intimm/dxh186
  4. Akira, S., Uematsu, S. & Takeuchi, O. Pathogen recognition and innate immunity. Cell 124:783-801 (2006) https://doi.org/10.1016/j.cell.2006.02.015
  5. Fitzgerald, K. A. et al. IKKepsilon and TBK1 are essential components of the IRF3 signaling pathway. Nat Immunol 4:491-496 (2003) https://doi.org/10.1038/ni921
  6. Kawai, T. et al. 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)
  7. Gao, J. J. et al. 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)
  8. Jarup, L. Hazards of heavy metal contamination. Br Med Bull 68:167-182 (2003) https://doi.org/10.1093/bmb/ldg032
  9. Christensen, M. M., Ellermann-Eriksen, S., Rungby, J. & Mogensen, S. C. Influence of mercuric chloride on resistance to generalized infection with herpes simplex virus type 2 in mice. Toxicology 114:57-66 (1996) https://doi.org/10.1016/S0300-483X(96)03409-9
  10. Elliott, P. et al. Risk of mortality, cancer incidence, and stroke in a population potentially exposed to cadmium. Occup Environ Med 57:94-97 (2000) https://doi.org/10.1136/oem.57.2.94
  11. Buchet, J. P. et al. Renal effects of cadmium body burden of the general population. Lancet 336:699-702 (1990) https://doi.org/10.1016/0140-6736(90)92201-R
  12. Alfven, T. et al. Low-level cadmium exposure and osteoporosis. J Bone Miner Res 15:1579-1586 (2000) https://doi.org/10.1359/jbmr.2000.15.8.1579
  13. Kolonel, L. N. Association of cadmium with renal cancer. Cancer 37:1782-1787 (1976) https://doi.org/10.1002/1097-0142(197604)37:4<1782::AID-CNCR2820370424>3.0.CO;2-F
  14. Mandel, J. S. et al. International renal-cell cancer study. IV. Occupation. Int J Cancer 61:601-605 (1995) https://doi.org/10.1002/ijc.2910610503
  15. Shukla, A., Shukla, G. S. & Srimal, R. C. Cadmiuminduced alterations in blood-brain barrier permeability and its possible correlation with decreased microvessel antioxidant potential in rat. Hum Exp Toxicol 15:400-405 (1996) https://doi.org/10.1177/096032719601500507
  16. Zalups, R. K. & Ahmad, S. Molecular handling of cadmium in transporting epithelia. Toxicol Appl Pharmacol 186:163-188 (2003) https://doi.org/10.1016/S0041-008X(02)00021-2
  17. Kawai, T. & Akira, S. Signaling to NF-kappaB by Toll-like receptors. Trends Mol Med 13:460-469 (2007) https://doi.org/10.1016/j.molmed.2007.09.002
  18. Zandi, E., Rothwarf, D. M., Delhase, M., Hayakawa, M. & Karin, M. The IkappaB kinase complex (IKK) contains two kinase subunits, IKKalpha and IKKbeta, necessary for IkappaB phosphorylation and NF-kappaB activation. Cell 91:243-252 (1997) https://doi.org/10.1016/S0092-8674(00)80406-7
  19. Yamaoka, S. et al. Complementation cloning of NEMO, a component of the IkappaB kinase complex essential for NF-kappaB activation. Cell 93:1231-1240 (1998) https://doi.org/10.1016/S0092-8674(00)81466-X
  20. Lin, R., Heylbroeck, C., Pitha, P. M. & Hiscott, J. Virus-dependent phosphorylation of the IRF-3 transcription factor regulates nuclear translocation, transactivation potential, and proteasome-mediated degradation. Mol Cell Biol 18:2986-2996 (1998) https://doi.org/10.1128/MCB.18.5.2986
  21. Navarro, L. & David, M. p38-dependent activation of interferon regulatory factor 3 by lipopolysaccharide. J Biol Chem 274:35535-35538 (1999) https://doi.org/10.1074/jbc.274.50.35535
  22. Lin, R., Heylbroeck, C., Genin, P., Pitha, P. M. & Hiscott, J. Essential role of interferon regulatory factor 3 in direct activation of RANTES chemokine transcription. Mol Cell Biol 19:959-966 (1999) https://doi.org/10.1128/MCB.19.2.959
  23. Schafer, S. L., Lin, R., Moore, P. A., Hiscott, J. & Pitha, P. M. Regulation of type I interferon gene expression by interferon regulatory factor-3. J Biol Chem 273:2714-2720 (1998) https://doi.org/10.1074/jbc.273.5.2714
  24. Honda, K. & Taniguchi, T. IRFs: master regulators of signalling by Toll-like receptors and cytosolic patternrecognition receptors. Nat Rev Immunol 6:644-658 (2006) https://doi.org/10.1038/nri1900
  25. Bjorkbacka, H. et al. The induction of macrophage gene expression by LPS predominantly utilizes Myd88-independent signaling cascades. Physiol Genomics 19:319-330 (2004) https://doi.org/10.1152/physiolgenomics.00128.2004
  26. Manca, D., Ricard, A. C., Tra, H. V. & Chevalier, G. Relation between lipid peroxidation and inflammation in the pulmonary toxicity of cadmium. Arch Toxicol 68:364-369 (1994) https://doi.org/10.1007/s002040050083
  27. Stohs, S. J. & Bagchi, D. Oxidative mechanisms in the toxicity of metal ions. Free Radic Biol Med 18:321-336 (1995) https://doi.org/10.1016/0891-5849(94)00159-H
  28. Hanas, J. S. & Gunn, C. G. Inhibition of transcription factor IIIA-DNA interactions by xenobiotic metal ions. Nucleic Acids Res 24:924-930 (1996) https://doi.org/10.1093/nar/24.5.924
  29. Splittgerber, A. G. & Tappel, A. L. Inhibition of glutathione peroxidase by cadmium and other metal ions. Arch Biochem Biophys 197:534-542 (1979) https://doi.org/10.1016/0003-9861(79)90277-7
  30. Shumilla, J. A., Wetterhahn, K. E. & Barchowsky, A. Inhibition of NF-kappa B binding to DNA by chromium, cadmium, mercury, zinc, and arsenite in vitro: evidence of a thiol mechanism. Arch Biochem Biophys 349:356-362 (1998) https://doi.org/10.1006/abbi.1997.0470
  31. Ahn, S. I., Park, S. K., Lee, M. Y. & Youn, H. S. Cadmium but not mercury suppresses NF-kB activation and COX-2 expression induced by Toll-like receptor 2 and 4 agonists. Mol Cell Toxicol 5:141-146 (2009)
  32. Youn, H. S., Ahn, S. I. & Lee, B. Y. Guggulsterone suppresses the activation of transcription factor IRF3 induced by TLR3 or TLR4 agonists. Int Immunopharmacol 9:108-112 (2009) https://doi.org/10.1016/j.intimp.2008.10.012
  33. Ahn, S. I., Lee, J. K. & Youn, H. S. Inhibition of homodimerization of toll-like receptor 4 by 6-shogaol. Mol Cells 27:211-215 (2009) https://doi.org/10.1007/s10059-009-0026-y
  34. Youn, H. S. et al. Specific inhibition of MyD88-independent signaling pathways of TLR3 and TLR4 by resveratrol: molecular targets are TBK1 and RIP1 in TRIF complex. J Immunol 175:3339-3346 (2005) https://doi.org/10.4049/jimmunol.175.5.3339
  35. Youn, H. S., Saitoh, S. I., Miyake, K. & Hwang, D. H. Inhibition of homodimerization of Toll-like receptor 4 by curcumin. Biochem Pharmacol 72:62-69 (2006) https://doi.org/10.1016/j.bcp.2006.03.022