title: Stimulation of TRAF6/TAK1 degradation and inhibition of JNK/AP-1 signalling by ginsenoside Rg3 attenuates hepatitis B virus replication.
abstract: In present study, we investigated the effect of ginsenoside Rg3 on hepatitis B virus DNA replication and secretion of hepatitis B surface antigen and e antigen in HepG2.2.15 cells. Rg3 dose- and time-dependently inhibited hepatitis B surface antigen, e antigen, and hepatitis B viral particle secretion. To explore the effect of Rg3 on anti-hepatitis B activity, we analysed toll-like receptor-myeloid differentiation primary response gene 88 signalling. Rg3 did not affect the expression of toll-like receptors or myeloid differentiation primary response gene 88. However, it significantly inhibited the expression of TNF receptor-associated factor 6 and transforming growth factor β activated kinase-1, which are adaptor molecules that signal through a toll-like receptor-myeloid differentiation primary response gene 88-dependent pathway. The inhibitory effect of Rg3 on TNF receptor-associated factor 6/transforming growth factor β activated kinase-1 expression was caused by the downregulation of TNF receptor-associated factor 6 expression as well as the stimulation of ubiquitination and proteasomal degradation of TNF receptor-associated factor 6, followed by downregulation of transforming growth factor β activated kinase-1. Furthermore, Rg3 inhibited mitogen-activated protein kinase signalling by inhibiting c-Jun N-terminal kinase phosphorylation, reduced the expression of AP-1 transcription factors (especially c-Jun and JunB), and inhibited AP-1 promoter activity. The inhibitory effect of Rg3 on c-Jun N-terminal kinase/AP-1 signalling showed anti-inflammatory activity based on the reduction in the expression of pro-inflammatory cytokines, IL-8 and TNF-α, at both the transcriptional and translational levels. Therefore, Rg3 showed anti-hepatitis B activity via the degradation of TNF receptor-associated factor 6/transforming growth factor β activated kinase-1 and the inhibition of c-Jun N-terminal kinase/AP-1 signalling.
authors.affiliation: Department of Biotechnology, Bioenergy Research Center, Chonnam National University, Gwangju 500-757, South Korea.
authors.forename: Li-Jung
authors.initials: LJ
authors.lastname: Kang
authors.forename: Yeo-Jin
authors.initials: YJ
authors.lastname: Choi
authors.forename: Seong-Gene
authors.initials: SG
authors.lastname: Lee
mesh_terms: D000998:Antiviral Agents / Q000494:pharmacology; D016207:Cytokines / Q000378:metabolism; D055785:Gene Knockdown Techniques; D036145:Ginsenosides / Q000494:pharmacology*; D056945:Hep G2 Cells; D006514:Hepatitis B Surface Antigens / Q000378:metabolism; D006513:Hepatitis B e Antigens / Q000378:metabolism; D006515:Hepatitis B virus / Q000187:drug effects / Q000254:growth & development / Q000502:physiology*; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D020930:MAP Kinase Kinase Kinases / Q000378:metabolism*; D020935:MAP Kinase Signaling System / Q000187:drug effects; D053594:Myeloid Differentiation Factor 88 / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D011401:Promoter Regions, Genetic / Q000235:genetics; D059748:Proteolysis / Q000187:drug effects*; D048029:TNF Receptor-Associated Factor 6 / Q000378:metabolism*; D051193:Toll-Like Receptors / Q000235:genetics / Q000378:metabolism; D018808:Transcription Factor AP-1 / Q000235:genetics / Q000378:metabolism*; D054875:Ubiquitination / Q000187:drug effects; D014779:Virus Replication / Q000187:drug effects*; D000099151:MAP Kinase Kinase Kinase 7
chemical_list: D000998:Antiviral Agents; D016207:Cytokines; D036145:Ginsenosides; D006514:Hepatitis B Surface Antigens; D006513:Hepatitis B e Antigens; D048031:JNK Mitogen-Activated Protein Kinases; D020930:MAP Kinase Kinase Kinases; D053594:Myeloid Differentiation Factor 88; D048029:TNF Receptor-Associated Factor 6; D051193:Toll-Like Receptors; D018808:Transcription Factor AP-1; D000099151:MAP Kinase Kinase Kinase 7; C097367:ginsenoside Rg3
keywords: Ginsenoside Rg3; Hepatitis B virus; TAK1; TRAK6; Ubiquitination