Halofuginone ameliorates inflammation in severe acute hepatitis B virus (HBV)-infected SD rats through AMPK activation

Drug Des Devel Ther. 2017 Oct 10:11:2947-2955. doi: 10.2147/DDDT.S149623. eCollection 2017.

Abstract

The hepatitis B virus (HBV) has caused acute and chronic liver diseases in ~350 million infected people worldwide. Halofuginone (HF) is a plant alkaloid which has been demonstrated to play a crucial role in immune regulation. Our present study explored the function of HF in the immune response of HBV-infected Sprague Dawley (SD) rats. Plasmid containing pCDNA3.1-HBV1.3 was injected in SD rats for the construction of an acute HBV-infected animal model. Our data showed that HF reduced the high concentrations of serum hepatitis B e-antigen, hepatitis B surface antigen, and HBV DNA induced by HBV infection. HF also reduced the number of T helper (Th)17 cells and the expression of interleukin (IL)-17 compared with the pCDNA3.1-HBV1.3 group. Moreover, pro-inflammatory cytokine levels (IL-17, IL-23, interferon-γ, and IL-2) were downregulated and anti-inflammatory cytokine levels (IL-4 and IL-13) were upregulated by HF. Through further research we found that the expression of AMP-activated protein kinase (AMPK) and IKBA which suppressed NF-κB activation was increased while the expression of p-NF-κB P65 was decreased in pCDNA3.1-HBV1.3+HF group compared with pCDNA3.1-HBV1.3 group, indicating that HF may work through the activation of AMPK. Finally, our conjecture was further verified by using the AMPK inhibitor compound C, which counteracted the anti-inflammation effect of HF, resulting in the decreased expression of AMPK, IKBA and increased expression of p-NF-κB P65 and reduced number of Th17 cells. In our present study, HF was considered as an anti-inflammatory factor in acute HBV-infected SD rats and worked through AMPK-mediated NF-κB p65 inactivation. This study implicated HF as a potential therapeutic strategy for hepatitis B.

Keywords: AMPK; halofuginone; hepatitis B virus; inflammation.

MeSH terms

  • AMP-Activated Protein Kinases / metabolism
  • Acute Disease
  • Animals
  • Anti-Inflammatory Agents / pharmacology*
  • Cytokines / metabolism
  • DNA, Viral / blood
  • Disease Models, Animal
  • Female
  • Hepatitis B / drug therapy*
  • Hepatitis B / immunology
  • Hepatitis B / pathology
  • Hepatitis B Surface Antigens / blood
  • Hepatitis B e Antigens / blood
  • Inflammation / drug therapy*
  • Inflammation / immunology
  • Inflammation / virology
  • Piperidines / pharmacology*
  • Quinazolinones / pharmacology*
  • Rats
  • Rats, Sprague-Dawley
  • Severity of Illness Index
  • Transcription Factor RelA / metabolism

Substances

  • Anti-Inflammatory Agents
  • Cytokines
  • DNA, Viral
  • Hepatitis B Surface Antigens
  • Hepatitis B e Antigens
  • Piperidines
  • Quinazolinones
  • Transcription Factor RelA
  • AMP-Activated Protein Kinases
  • halofuginone