title: Hepatitis B Virus Middle Protein Enhances IL-6 Production via p38 MAPK/NF-κB Pathways in an ER Stress-Dependent Manner.
abstract: During hepatitis B virus (HBV) infection, three viral envelope proteins of HBV are overexpressed in the endoplasmic reticulum (ER). The large S protein (LHBs) and truncated middle S protein (MHBst) have been documented to play roles in regulating host gene expression and contribute to hepatic disease development. As a predominant protein at the ultrastructural level in biopsy samples taken from viremic patients, the role of the middle S protein (MHBs) remains to be understood despite its high immunogenicity. When we transfected hepatocytes with an enhanced green fluorescent protein (EGFP)-tagged MHBs expressing plasmid, the results showed that expression of MHBs cause an upregulation of IL-6 at the message RNA and protein levels through activating the p38 mitogen-activated protein kinase (p38 MAPK) and nuclear factor-kappa B (NF-κB) pathways. The use of specific inhibitors of the signaling pathways can diminish this upregulation. The use of BAPTA-AM attenuated the stimulation caused by MHBs. We further found that MHBs accumulated in the endoplasmic reticulum and increased the amount of glucose regulated protein 78 (GRP78/BiP). Our results provide a possibility that MHBs could be involved in liver disease progression.
authors.affiliation: State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Institute of Infectious Diseases, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.|Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Hangzhou, China.|School of Medicine, Zhejiang University, Hangzhou, China.
authors.forename: Yang-Xia
authors.initials: YX
authors.lastname: Li
authors.affiliation: State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Institute of Infectious Diseases, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.|Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Hangzhou, China.|School of Medicine, Zhejiang University, Hangzhou, China.
authors.forename: Yan-Li
authors.initials: YL
authors.lastname: Ren
authors.affiliation: State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Institute of Infectious Diseases, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.|Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Hangzhou, China.|School of Medicine, Zhejiang University, Hangzhou, China.
authors.forename: Hai-Jing
authors.initials: HJ
authors.lastname: Fu
authors.affiliation: State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Institute of Infectious Diseases, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.|Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Hangzhou, China.|School of Medicine, Zhejiang University, Hangzhou, China.
authors.forename: Ling
authors.initials: L
authors.lastname: Zou
authors.affiliation: State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Institute of Infectious Diseases, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.|Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Hangzhou, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Yang
authors.affiliation: State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Institute of Infectious Diseases, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.|Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Hangzhou, China.|School of Medicine, Zhejiang University, Hangzhou, China.
authors.forename: Zhi
authors.initials: Z
authors.lastname: Chen
mesh_terms: D002460:Cell Line; D004721:Endoplasmic Reticulum / Q000235:genetics / Q000821:virology; D000091342:Endoplasmic Reticulum Chaperone BiP; D059865:Endoplasmic Reticulum Stress / Q000235:genetics; D015967:Gene Expression Regulation, Viral; D049452:Green Fluorescent Proteins / Q000235:genetics; D006509:Hepatitis B / Q000235:genetics* / Q000473:pathology / Q000821:virology*; D006515:Hepatitis B virus / Q000235:genetics* / Q000472:pathogenicity; D054884:Host-Pathogen Interactions / Q000235:genetics*; D006801:Humans; D015850:Interleukin-6 / Q000096:biosynthesis; D016328:NF-kappa B / Q000235:genetics; D010766:Phosphorylation / Q000235:genetics; D015398:Signal Transduction; D051996:Transcription Factor RelA / Q000235:genetics; D014759:Viral Envelope Proteins / Q000096:biosynthesis / Q000235:genetics*; D048051:p38 Mitogen-Activated Protein Kinases / Q000235:genetics
chemical_list: D000091342:Endoplasmic Reticulum Chaperone BiP; C000717247:HSPA5 protein, human; D015850:Interleukin-6; D016328:NF-kappa B; C498143:RELA protein, human; D051996:Transcription Factor RelA; D014759:Viral Envelope Proteins; D049452:Green Fluorescent Proteins; D048051:p38 Mitogen-Activated Protein Kinases