title: The SMAC mimetic birinapant attenuates lipopolysaccharide-induced liver injury by inhibiting the tumor necrosis factor receptor-associated factor 3 degradation in Kupffer cells.
abstract: It was demonstrated that second mitochondria-derived activator of caspases (SMAC) mimetic inhibites tumor necrosis factor receptor-associated factor 3 (TRAF3) degradation and the mitogen-activated protein kinase (MAPK) signaling pathway activation induced by lipopolysaccharide (LPS) in vitro. However, the effect of Smac mimetic in vivo is not clear. The present study was to investigate the role of Smac mimetic in LPS-induced liver injury in mice and its possible mechanism. An animal model of LPS-induced liver injury was established by intraperitoneally injecting mice with 10mg/kg LPS pretreatment with or without Smac mimetic birinapant (30mg/kg body weight). Birinapant significantly improved the survival rate of endotoxemic mice (P<0.05) and attenuated LPS-induced liver pathologic damage and inflammatory response. IL-1 and TNF-α levels in the serum were markedly decreased in birinapant pretreatment mice compared with control mice (P<0.05).The cellular inhibitor of apoptosis protein 1 (cIAP1) expression in liver resident macrophage (Kupffer cells, KCs) was significantly decreased in the Birinapant group compared to the Vehicle group (P<0.05). At the same time, total TRAF3 protein abundance in KCs rapidly declined after LPS stimulation in the Vehicle group. However, it remained constant in the Birinapant group. Moreover, K48-linked polyubiquitination of TRAF3 in KCs was markedly impressed in the birinapant group compared with the control group. At last, the JNK and p38 MAPK activation in KCs was significantly inhibited by birinapant pretreatment (P<0.05). These results suggested that birinapant attenuated liver injury and improved survival rates in endotoxemic mice by inhibited the expression of cIAP1, degradation of TRAF3 and aviation of MAPK signaling pathway.
authors.affiliation: Department of Hepatobiliary Surgery, The Second Affiliated Hospital of Chongqing Medical University, 74# Linjiang Road, Chongqing 400010, PR China.
authors.forename: Hongxiang
authors.initials: H
authors.lastname: Liu
authors.affiliation: Department of Hepatobiliary Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, PR China.
authors.forename: Rui
authors.initials: R
authors.lastname: Liao
authors.affiliation: Department of Hepatobiliary Surgery, The Second Affiliated Hospital of Chongqing Medical University, 74# Linjiang Road, Chongqing 400010, PR China.
authors.forename: Kun
authors.initials: K
authors.lastname: He
authors.affiliation: Department of Hepatobiliary Surgery, The Second Affiliated Hospital of Chongqing Medical University, 74# Linjiang Road, Chongqing 400010, PR China.
authors.forename: Xiwen
authors.initials: X
authors.lastname: Zhu
authors.affiliation: Department of Hepatobiliary Surgery, The Second Affiliated Hospital of Chongqing Medical University, 74# Linjiang Road, Chongqing 400010, PR China. Electronic address: lipeizhi@163.com.
authors.forename: Peizhi
authors.initials: P
authors.lastname: Li
authors.affiliation: Department of Hepatobiliary Surgery, The Second Affiliated Hospital of Chongqing Medical University, 74# Linjiang Road, Chongqing 400010, PR China. Electronic address: gongjianping11@126.com.
authors.forename: Jianping
authors.initials: J
authors.lastname: Gong
mesh_terms: D000818:Animals; D051017:Apoptosis Regulatory Proteins; D032701:Biomimetics; D002352:Carrier Proteins / Q000737:chemistry; D056486:Chemical and Drug Induced Liver Injury / Q000188:drug therapy*; D004151:Dipeptides / Q000737:chemistry / Q000627:therapeutic use*; D004195:Disease Models, Animal; D019446:Endotoxemia / Q000188:drug therapy*; D006801:Humans; D007211:Indoles / Q000737:chemistry / Q000627:therapeutic use*; D051034:Inhibitor of Apoptosis Proteins / Q000378:metabolism; D007375:Interleukin-1 / Q000097:blood; D007728:Kupffer Cells / Q000187:drug effects* / Q000276:immunology; D008070:Lipopolysaccharides / Q000276:immunology; D008099:Liver / Q000276:immunology / Q000473:pathology*; D020935:MAP Kinase Signaling System; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D024101:Mitochondrial Proteins / Q000737:chemistry; D059748:Proteolysis; D048008:TNF Receptor-Associated Factor 3 / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000097:blood; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism
chemical_list: D051017:Apoptosis Regulatory Proteins; D002352:Carrier Proteins; C499605:Diablo protein, mouse; D004151:Dipeptides; D007211:Indoles; D051034:Inhibitor of Apoptosis Proteins; D007375:Interleukin-1; D008070:Lipopolysaccharides; D024101:Mitochondrial Proteins; D048008:TNF Receptor-Associated Factor 3; D014409:Tumor Necrosis Factor-alpha; C582429:birinapant; C494834:Birc2 protein, mouse; D044767:Ubiquitin-Protein Ligases
keywords: Birinapant; Liver injury; Tumor necrosis factor receptor-associated factor 3; Ubiquitination