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Inflammation

, Volume 39, Issue 1, pp 96–106 | Cite as

Quercetin Protects Mice from ConA-Induced Hepatitis by Inhibiting HMGB1-TLR Expression and Down-Regulating the Nuclear Factor Kappa B Pathway

  • Xi Li
  • Hong-chun Liu
  • Qun-yan Yao
  • Bei-li Xu
  • Shun-cai Zhang
  • Chuan-tao Tu
Article

Abstract

The dietary flavonoid quercetin has hepatoprotective effects. We analyzed the effects of quercetin on concanavalin A (ConA)-induced hepatitis in mice and its underlying molecular mechanisms of action. Mice were administered quercetin (50 mg/kg body weight, i.p.) or vehicle 30 min before intravenous administration of ConA. Quercetin pretreatment significantly reduced the ConA-induced elevations in plasma aminotransferase concentrations and liver necrosis, as well as reducing serum concentrations of the pro-inflammatory cytokines tumor necrosis factor (TNF)-α, interferon-γ, and interleukin-4. Quercetin pretreatment also reduced expression of high-mobility group box 1 protein (HMGB1) and toll-like receptor (TLR)-2 and TLR-4 messenger RNA (mRNA) and protein in liver tissues. Quercetin pretreatment significantly inhibited degradation of inhibitory kappa B alpha and modulated ConA-induced nuclear translocation in the liver of nuclear factor kappa B (NF-κB) p65. These results demonstrate that quercetin protects against ConA-mediated hepatitis in mice by attenuating the HMGB1–TLRs–NF-κB signaling pathway.

KEY WORDS

quercetin hepatitis inflammation nuclear factor κB high-mobility group box 1 protein toll-like receptor 

Notes

Acknowledgments

This work was supported in part by the National Science Foundation of China (grant number 81170398) and the National Clinical Key Special Subject of China.

Conflict of Interest

The authors declare that there are no conflicts of interests regarding publication of this article.

References

  1. 1.
    Thimme, R., S. Wieland, C. Steiger, J. Ghrayeb, K.A. Reimann, R.H. Purcell, et al. 2003. CD8(+) T cells mediate viral clearance and disease pathogenesis during acute hepatitis B virus infection. Journal of Virology 77: 68–76.PubMedCentralCrossRefPubMedGoogle Scholar
  2. 2.
    Rehermann, B., and M. Nascimbeni. 2005. Immunology of hepatitis B virus and hepatitis C virus infection. Nature Reviews Immunology 5: 215–229.CrossRefPubMedGoogle Scholar
  3. 3.
    Heneghan, M.A., A.D. Yeoman, S. Verma, A.D. Smith, and M.S. Longhi. 2013. Autoimmune hepatitis. Lancet 382: 1433–1444.CrossRefPubMedGoogle Scholar
  4. 4.
    Tiegs, G., J. Hentschel, and A. Wendel. 1992. A T cell-dependent experimental liver injury in mice inducible by concanavalin A. Journal of Clinical Investigation 90: 196–203.PubMedCentralCrossRefPubMedGoogle Scholar
  5. 5.
    Ajuebor, M.N., J.A. Carey, and M.G. Swain. 2006. CCR5 in T cell-mediated liver diseases: what’s going on. Journal of Immunology 177: 2039–2045.CrossRefGoogle Scholar
  6. 6.
    Kawasuji, A., M. Hasegawa, M. Horikawa, T. Fujita, Y. Matsushita, T. Matsushita, et al. 2006. L-selectin and intercellular adhesion molecule-1 regulate the development of concanavalin A-induced liver injury. Journal of Leukocyte Biology 79: 696–705.CrossRefPubMedGoogle Scholar
  7. 7.
    Wang, H., O. Bloom, M. Zhang, J.M. Vishnubhakat, M. Ombrellino, J. Che, et al. 1999. HMG-1 as a late mediator of endotoxin lethality in mice. Science 285: 248–251.CrossRefPubMedGoogle Scholar
  8. 8.
    Lotze, M.T., and K.J. Tracey. 2005. High-mobility group box 1 protein (HMGB1): nuclear weapon in the immune arsenal. Nature Reviews Immunology 5: 331–342.CrossRefPubMedGoogle Scholar
  9. 9.
    Andersson, U., and K.J. Tracey. 2011. HMGB1 is a therapeutic target for sterile inflammation and infection. Annual Review of Immunology 29: 139–162.PubMedCentralCrossRefPubMedGoogle Scholar
  10. 10.
    Musumeci, D., G.N. Roviello, and D. Montesarchio. 2014. An overview on HMGB1 inhibitors as potential therapeutic agents in HMGB1-related pathologies. Pharmacology and Therapeutics 141: 347–357.CrossRefPubMedGoogle Scholar
  11. 11.
    Baldwin Jr., A.S. 1996. The NF-kappa B and I kappa B proteins: new discoveries and insights. Annual Review of Immunology 14: 649–683.CrossRefPubMedGoogle Scholar
  12. 12.
    Sass, G., S. Heinlein, A. Agli, R. Bang, J. Schumann, and G. Tiegs. 2002. Cytokine expression in three mouse models of experimental hepatitis. Cytokine 19: 115–120.CrossRefPubMedGoogle Scholar
  13. 13.
    Tsung, A., J.R. Klune, X. Zhang, G. Jeyabalan, Z. Cao, X. Peng, et al. 2007. HMGB1 release induced by liver ischemia involves Toll-like receptor 4 dependent reactive oxygen species production and calcium-mediated signaling. Journal of Experimental Medicine 204: 2913–2923.PubMedCentralCrossRefPubMedGoogle Scholar
  14. 14.
    Gong, Q., H. Zhang, J.H. Li, L.H. Duan, S. Zhong, X.L. Kong, et al. 2010. High-mobility group box 1 exacerbates concanavalin A-induced hepatic injury in mice. International Journal of Molecular Medicine (Berl) 88: 1289–1298.CrossRefGoogle Scholar
  15. 15.
    Takano, K., M. Shinoda, M. Tanabe, T. Miyasho, S. Yamada, S. Ono, et al. 2010. Protective effect of high-mobility group box 1 blockade on acute liver failure in rats. Shock 34: 573–579.CrossRefPubMedGoogle Scholar
  16. 16.
    Zhou, R.R., S.S. Zhao, M.X. Zou, P. Zhang, B.X. Zhang, X.H. Dai, et al. 2011. HMGB1 cytoplasmic translocation in patients with acute liver failure. BMC Gastroenterology 11: 21.PubMedCentralCrossRefPubMedGoogle Scholar
  17. 17.
    Tu, C.T., Q.Y. Yao, B.L. Xu, and S.C. Zhang. 2013. Curcumin protects against concanavalin A-induced hepatitis in mice through inhibiting the cytoplasmic translocation and expression of high mobility group box 1. Inflammation 36: 206–215.CrossRefPubMedGoogle Scholar
  18. 18.
    Schwabe, R.F., E. Seki, and D.A. Brenner. 2006. Toll-like receptor signaling in the liver. Gastroenterology 130: 1886–1900.CrossRefPubMedGoogle Scholar
  19. 19.
    Ojiro, K., H. Ebinuma, N. Nakamoto, K. Wakabayashi, Y. Mikami, Y. Ono, et al. 2010. MyD88-dependent pathway accelerates the liver damage of Concanavalin A-induced hepatitis. Biochemical and Biophysical Research Communications 399: 744–749.CrossRefPubMedGoogle Scholar
  20. 20.
    Takeuchi, O., and S. Akira. 2010. Pattern recognition receptors and inflammation. Cell 140: 805–820.CrossRefPubMedGoogle Scholar
  21. 21.
    Xu, J., X. Zhang, M. Monestier, N.L. Esmon, and C.T. Esmon. 2011. Extracellular histones are mediators of death through TLR2 and TLR4 in mouse fatal liver injury. Journal of Immunology 187: 2626–2631.CrossRefGoogle Scholar
  22. 22.
    Tu, C.T., B. Han, Q.Y. Yao, Y.A. Zhang, H.C. Liu, and S.C. Zhang. 2012. Curcumin attenuates Concanavalin A-induced liver injury in mice by inhibition of toll-like receptor (TLR) 2, TLR4 and TLR9 expression. International Immunopharmacology 12: 151–157.CrossRefPubMedGoogle Scholar
  23. 23.
    Formica, J.V., and W. Regelson. 1995. Review of the biology of quercetin and related bioflavonoids. Food and Chemical Toxicology 33: 1061–1080.CrossRefPubMedGoogle Scholar
  24. 24.
    Del, P.A., A. Scalera, M.D. Iadevaia, A. Miranda, C. Zulli, L. Gaeta, et al. 2012. Herbal products: benefits, limits, and applications in chronic liver disease. Evidence-based Complementary and Alternative Medicine 2012: 837939.Google Scholar
  25. 25.
    Bhaskar, S., V. Shalini, and A. Helen. 2011. Quercetin regulates oxidized LDL induced inflammatory changes in human PBMCs by modulating the TLR-NF-kappaB signaling pathway. Immunobiology 216: 367–373.CrossRefPubMedGoogle Scholar
  26. 26.
    Marcolin, E., B. San-Miguel, D. Vallejo, J. Tieppo, N. Marroni, J. Gonzalez-Gallego, et al. 2012. Quercetin treatment ameliorates inflammation and fibrosis in mice with nonalcoholic steatohepatitis. Journal of Nutrition 142: 1821–1828.CrossRefPubMedGoogle Scholar
  27. 27.
    Byun, E.B., M.S. Yang, H.G. Choi, N.Y. Sung, D.S. Song, S.J. Sin, et al. 2013. Quercetin negatively regulates TLR4 signaling induced by lipopolysaccharide through Tollip expression. Biochemical and Biophysical Research Communications 431: 698–705.CrossRefPubMedGoogle Scholar
  28. 28.
    Tang, D., R. Kang, W. Xiao, H. Zhang, M.T. Lotze, H. Wang, et al. 2009. Quercetin prevents LPS-induced high-mobility group box 1 release and proinflammatory function. American Journal of Respiratory Cell and Molecular Biology 41: 651–660.PubMedCentralCrossRefPubMedGoogle Scholar
  29. 29.
    Su, J.F., C.J. Guo, J.Y. Wei, J.J. Yang, Y.G. Jiang, and Y.F. Li. 2003. Protection against hepatic ischemia-reperfusion injury in rats by oral pretreatment with quercetin. Biomedical and Environmental Sciences 16: 1–8.PubMedGoogle Scholar
  30. 30.
    de David, C., G. Rodrigues, S. Bona, L. Meurer, J. Gonzalez-Gallego, M.J. Tunon, et al. 2011. Role of quercetin in preventing thioacetamide-induced liver injury in rats. Toxicologic Pathology 39: 949–957.CrossRefPubMedGoogle Scholar
  31. 31.
    Domitrovic, R., H. Jakovac, M.V. Vasiljev, S. Vladimir-Knezevic, O. Cvijanovic, Z. Tadic, et al. 2012. Differential hepatoprotective mechanisms of rutin and quercetin in CCl (4)-intoxicated BALB/cN mice. Acta Pharmacologica Sinica 33: 1260–1270.PubMedCentralCrossRefPubMedGoogle Scholar
  32. 32.
    Yumoto, E., T. Higashi, K. Nouso, H. Nakatsukasa, K. Fujiwara, T. Hanafusa, et al. 2002. Serum gamma-interferon-inducing factor (IL-18) and IL-10 levels in patients with acute hepatitis and fulminant hepatic failure. Journal of Gastroenterology and Hepatology 17: 285–294.CrossRefPubMedGoogle Scholar
  33. 33.
    Castellano-Higuera, A., E. Gonzalez-Reimers, M.R. Aleman-Valls, P. Abreu-Gonzalez, F. Santolaria-Fernandez, M.J. De La Vega-Prieto, et al. 2008. Cytokines and lipid peroxidation in alcoholics with chronic hepatitis C virus infection. Alcohol and Alcoholism 43: 137–142.CrossRefPubMedGoogle Scholar
  34. 34.
    Zou, Z., B. Li, D. Xu, Z. Zhang, J.M. Zhao, G. Zhou, et al. 2009. Imbalanced intrahepatic cytokine expression of interferon-gamma, tumor necrosis factor-alpha, and interleukin-10 in patients with acute-on-chronic liver failure associated with hepatitis B virus infection. Journal of Clinical Gastroenterology 43: 182–190.CrossRefPubMedGoogle Scholar
  35. 35.
    Park, J.S., D. Svetkauskaite, Q. He, J.Y. Kim, D. Strassheim, A. Ishizaka, et al. 2004. Involvement of toll-like receptors 2 and 4 in cellular activation by high mobility group box 1 protein. Journal of Biological Chemistry 279: 7370–7377.CrossRefPubMedGoogle Scholar
  36. 36.
    Chen, Y., and R. Sun. 2011. Toll-like receptors in acute liver injury and regeneration. International Immunopharmacology 11: 1433–1441.CrossRefPubMedGoogle Scholar
  37. 37.
    Uesugi, T., M. Froh, G.E. Arteel, B.U. Bradford, and R.G. Thurman. 2001. Toll-like receptor 4 is involved in the mechanism of early alcohol-induced liver injury in mice. Hepatology 34: 101–108.CrossRefPubMedGoogle Scholar
  38. 38.
    Xiao, X., P. Zhao, D. Rodriguez-Pinto, D. Qi, O. Henegariu, L. Alexopoulou, et al. 2009. Inflammatory regulation by TLR3 in acute hepatitis. Journal of Immunology 183: 3712–3719.CrossRefGoogle Scholar
  39. 39.
    Luedde, T., and R.F. Schwabe. 2011. NF-kappaB in the liver—linking injury, fibrosis and hepatocellular carcinoma. Nature Reviews Gastroenterology & Hepatology 8: 108–118.CrossRefGoogle Scholar
  40. 40.
    Schumann, J., J. Prockl, A.K. Kiemer, A.M. Vollmar, R. Bang, and G. Tiegs. 2003. Silibinin protects mice from T cell-dependent liver injury. Journal of Hepatology 39: 333–340.CrossRefPubMedGoogle Scholar
  41. 41.
    Hoffmann, F., G. Sass, J. Zillies, S. Zahler, G. Tiegs, A. Hartkorn, et al. 2009. A novel technique for selective NF-kappaB inhibition in Kupffer cells: contrary effects in fulminant hepatitis and ischaemia-reperfusion. Gut 58: 1670–1678.CrossRefPubMedGoogle Scholar
  42. 42.
    Comalada, M., D. Camuesco, S. Sierra, I. Ballester, J. Xaus, J. Galvez, et al. 2005. In vivo quercitrin anti-inflammatory effect involves release of quercetin, which inhibits inflammation through down-regulation of the NF-kappaB pathway. European Journal of Immunology 35: 584–592.CrossRefPubMedGoogle Scholar
  43. 43.
    Bharrhan, S., K. Chopra, S.K. Arora, J.S. Toor, and P. Rishi. 2012. Down-regulation of NF-kappaB signalling by polyphenolic compounds prevents endotoxin-induced liver injury in a rat model. Innate Immunity 18: 70–79.CrossRefPubMedGoogle Scholar
  44. 44.
    Liu, H., C.R. Lo, and M.J. Czaja. 2002. NF-kappaB inhibition sensitizes hepatocytes to TNF-induced apoptosis through a sustained activation of JNK and c-Jun. Hepatology 35: 772–778.CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2015

Authors and Affiliations

  • Xi Li
    • 1
    • 2
  • Hong-chun Liu
    • 1
    • 3
  • Qun-yan Yao
    • 1
    • 3
  • Bei-li Xu
    • 1
    • 3
  • Shun-cai Zhang
    • 1
    • 3
  • Chuan-tao Tu
    • 1
    • 3
  1. 1.Department of Gastroenterology and Hepatology, Zhongshan HospitalFudan UniversityShanghaiChina
  2. 2.Department of Geriatrics, Zhongshan HospitalFudan UniversityShanghaiChina
  3. 3.Shanghai Institute of Liver DiseasesShanghaiChina

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