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Hepatitis B Virus Middle Protein Enhances IL-6 Production via p38 MAPK/NF-κB Pathways in an ER Stress-Dependent

Yang-Xia Li1,2,3, Yan-Li Ren1,2,3, Hai-Jing Fu1,2,3

  • 1State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Institute of Infectious Diseases, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.

Plos One
|July 20, 2016
PubMed

Insights

Hepatitis B virus middle S protein (MHBs) upregulates IL-6 via p38 MAPK and NF-κB pathways, potentially contributing to liver disease progression. MHBs accumulation in the endoplasmic reticulum also increases GRP78/BiP levels.

Area of Science:

  • Hepatology
  • Virology
  • Molecular Biology

Background:

  • Hepatitis B virus (HBV) infection involves overexpression of three viral envelope proteins in the endoplasmic reticulum (ER).
  • The middle S protein (MHBs) is highly immunogenic and predominant in viremic patients, but its role in liver disease remains unclear.
  • Previous studies implicated large S (LHBs) and truncated middle S (MHBst) proteins in host gene regulation and hepatic disease.

Purpose of the Study:

  • To investigate the role of the middle S protein (MHBs) in hepatitis B virus infection.
  • To elucidate the molecular mechanisms by which MHBs influences host gene expression and cellular pathways.
  • To determine the potential involvement of MHBs in the progression of liver disease.

Main Methods:

  • Transfection of hepatocytes with an EGFP-tagged MHBs expressing plasmid.
  • Analysis of interleukin-6 (IL-6) mRNA and protein levels.
  • Assessment of p38 mitogen-activated protein kinase (p38 MAPK) and nuclear factor-kappa B (NF-κB) pathway activation.
  • Use of specific pathway inhibitors and BAPTA-AM to study signaling.
  • Evaluation of MHBs accumulation in the ER and its effect on glucose regulated protein 78 (GRP78/BiP).

Main Results:

  • MHBs expression led to upregulation of IL-6 at both mRNA and protein levels.
  • This upregulation was mediated by the activation of the p38 MAPK and NF-κB signaling pathways.
  • Inhibition of these pathways diminished the MHBs-induced IL-6 increase.
  • MHBs accumulation was observed in the ER, correlating with increased GRP78/BiP levels.
  • BAPTA-AM treatment attenuated the stimulation caused by MHBs.

Conclusions:

  • MHBs plays a significant role in modulating host inflammatory responses during HBV infection.
  • Activation of p38 MAPK and NF-κB pathways by MHBs contributes to IL-6 production.
  • MHBs-induced ER stress, indicated by GRP78/BiP increase, may be linked to liver disease pathogenesis.
  • These findings suggest MHBs is a potential factor in the progression of hepatitis B-related liver diseases.

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