title: Down-regulation of nuclear HMGB1 reduces ischemia-induced HMGB1 translocation and release and protects against liver ischemia-reperfusion injury.
abstract: Hepatocyte-specific HMGB1 deletion has been found to worsen the injury and inflammation in liver ischemia-reperfusion injury (IRI), highlighting a role for intracellular HMGB1 in cellular protection. Down-regulation of nuclear HMGB1 by small interfering RNA (siRNA) might not only decrease its injurious extracellular role by reducing its release but also serve to maintain its beneficial intracellular role, thus protecting against IRI. We established a non-lethal liver IRI model in mice via segmental hepatic warm ischemia for 1 h and reperfusion for 6 h. HMGB1-siRNA achieved a reduction of ~60-70% in the nuclear HMGB1 expression in the liver at 48 h post-treatment. Knockdown of nuclear HMGB1 expression dramatically reduced both the degree of nuclear-cytoplasmic translocation of HMGB1 during hepatic ischemia and of HMGB1 release after hepatic reperfusion, resulting in significant preservation of liver function and a marked reduction in pathological damage. Also, HMGB1-siRNA pretreatment markedly inhibited the increases in hepatic expression of TLR4, TLR2, RAGE, TNF-α, IL-1β, IL-6, MCP-1, iNOS, and COX-2 seen in control mice after hepatic reperfusion. We demonstrated for the first time that down-regulation of nuclear HMGB1 reduces ischemia-induced HMGB1 release and protects against liver IRI, which is helpful for better understanding the role of HMGB1 in organ IRI.
authors.affiliation: Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
authors.forename: Guangyuan
authors.initials: G
authors.lastname: Zhao
authors.affiliation: Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
authors.forename: Cheng
authors.initials: C
authors.lastname: Fu
authors.affiliation: Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.|Key Laboratory of Organ Transplantation, Ministry of Health, China.
authors.forename: Lu
authors.initials: L
authors.lastname: Wang
authors.affiliation: Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.|Key Laboratory of Organ Transplantation, Ministry of Health, China.
authors.forename: Lan
authors.initials: L
authors.lastname: Zhu
authors.affiliation: Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
authors.forename: Yutao
authors.initials: Y
authors.lastname: Yan
authors.affiliation: Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.|Key Laboratory of Organ Transplantation, Ministry of Health, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Xiang
authors.affiliation: Key Laboratory of Organ Transplantation, Ministry of Education, China.|Department of Immunology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
authors.forename: Fang
authors.initials: F
authors.lastname: Zheng
authors.affiliation: Key Laboratory of Organ Transplantation, Ministry of Education, China.|Department of Immunology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
authors.forename: Feili
authors.initials: F
authors.lastname: Gong
authors.affiliation: Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.|Key Laboratory of Organ Transplantation, Ministry of Health, China.
authors.forename: Song
authors.initials: S
authors.lastname: Chen
authors.affiliation: Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.|Key Laboratory of Organ Transplantation, Ministry of Health, China.
authors.forename: Gang
authors.initials: G
authors.lastname: Chen
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics; D002467:Cell Nucleus / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D005786:Gene Expression Regulation; D055785:Gene Knockdown Techniques; D020868:Gene Silencing; D024243:HMGB1 Protein / Q000235:genetics* / Q000378:metabolism*; D022781:Hepatocytes / Q000378:metabolism; D018836:Inflammation Mediators / Q000378:metabolism; D008099:Liver / Q000378:metabolism* / Q000473:pathology; D008111:Liver Function Tests; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D021381:Protein Transport; D034741:RNA, Small Interfering / Q000235:genetics; D015427:Reperfusion Injury / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology
chemical_list: D016207:Cytokines; D024243:HMGB1 Protein; D018836:Inflammation Mediators; D034741:RNA, Small Interfering