Quercetin Protects Mice from ConA-Induced Hepatitis by Inhibiting HMGB1-TLR Expression and Down-Regulating the Nuclear Factor Kappa B Pathway
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 WORDSquercetin hepatitis inflammation nuclear factor κB high-mobility group box 1 protein toll-like receptor
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.
- 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
- 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
- 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
- 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
- 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