title: The role of intracellular high-mobility group box 1 in the early activation of Kupffer cells and the development of Con A-induced acute liver failure.
abstract: Acute liver failure (ALF) is a highly complex syndrome characterized by devastating activation of early activation of Kupffer cells (KCs) has been implicated in the pathogenesis of ALF. However, the factors regulating KC early activation are virtually unexplored. The aim of present study was to determine the role of the intracellular high-mobility group box 1 (HMGB1) in modulating the early activation of KCs during ALF. The intravenous injection of Concanavalin A (Con A) was used to establish a mouse model of ALF. The dynamic pro-inflammatory properties and MHC II expression of KCs were measured by qRT-PCR and flow cytometry. HMGB1 expression in KCs was measured by qRT-PCR and Western blotting. The immunofluorescence was implemented to determine the relocation of HMGB1 in KCs, and the siRNA against HMGB1 was utilized to assess the impact of HMGB1 on KC pro-inflammatory properties. The peak of pro-inflammatory cytokines production and MHC II expression in KCs appeared at the early stage of ALF. The up-regulation of HMGB1 expression and the translocation of HMGB1 in KCs were in parallel with the early activation of KCs. The blockade of intracellular HMGB1 expression caused by siRNA significantly inhibited the production of KC-derived pro-inflammatory cytokines, and led to a down-regulation of MAP kinase activation in KCs. The self-derived HMGB1 is an "early alarmin" of KC activation during Con A-induced ALF. HMGB1 might be a potential target for cell-specific strategy in ALF.
authors.affiliation: State Key Laboratory of Infectious Disease Diagnosis and Treatment, First Affiliated Hospital, Medical College, Zhejiang University, Zhejiang, PR China.
authors.forename: Qiao
authors.initials: Q
authors.lastname: Yang
authors.forename: Yanning
authors.initials: Y
authors.lastname: Liu
authors.forename: Yu
authors.initials: Y
authors.lastname: Shi
authors.forename: Min
authors.initials: M
authors.lastname: Zheng
authors.forename: Jiliang
authors.initials: J
authors.lastname: He
authors.forename: Zhi
authors.initials: Z
authors.lastname: Chen
mesh_terms: D000818:Animals; D002467:Cell Nucleus / Q000378:metabolism*; D003208:Concanavalin A / Q000276:immunology; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D024243:HMGB1 Protein / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism; D007728:Kupffer Cells / Q000187:drug effects / Q000276:immunology*; D017114:Liver Failure, Acute / Q000276:immunology*; D020935:MAP Kinase Signaling System / Q000235:genetics; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D058990:Molecular Targeted Therapy; D021381:Protein Transport; D034741:RNA, Small Interfering / Q000235:genetics; D015854:Up-Regulation
chemical_list: D016207:Cytokines; D024243:HMGB1 Protein; D018836:Inflammation Mediators; D034741:RNA, Small Interfering; D003208:Concanavalin A
keywords: 4′,6-diamidino-2-phenylindole; ALF; ALT; ANOVA; AST; Acute liver failure; Apoptosis; BSA; Con A; Concanavalin A; DAPI; ELISA; ERK; GAPDH; HMGB1; High-mobility group box 1; IL; Inflammation; KC; Kupffer cell; Kupffer cells; MAPK; MHC II; MNC; PBS; RNA; RT-PCR; SD; SDS-PAGE; TBST; TNF-α; acute liver failure; alanine aminotransferase; analysis of variance; aspartate aminotransferase; bovine serum albumin; enzyme-linked immunosorbent assay; extracellular signal-regulated kinase; glyceraldehyde-3-phosphate dehydrogenase; high-mobility group box 1; interleukin; major histocompatibility complex class II; mitogen-activated protein kinase; mononuclear cell; phosphate-buffered saline; reverse transcription-polymerase chain reaction; ribonucleic acid; siRNA; small interfering ribonucleic acid; sodium dodecyl sulfate-polyacrylamide gel electrophoresis; standard deviation; tris-buffered saline tween-20; tumor necrosis factor-alpha