期刊
IMMUNOLOGY LETTERS
卷 185, 期 -, 页码 79-83出版社
ELSEVIER SCIENCE BV
DOI: 10.1016/j.imlet.2017.02.016
关键词
Birinapant; Tumor necrosis factor receptor-associated; factor 3; Ubiquitination; Liver injury
类别
资金
- National Natural Science Foundation of China [81401622, 31370753, 81301656, 81400614]
- Basic Science and Frontier Technology Research Foundation of Chongqing Science and Technology Commission [cstc2015jcy jBX0070]
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 10 mg/kg LPS pretreatment with or without Smac mimetic birinapant (30 mg/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-alpha levels in the serum were markedly decreased in birinapant pretreatment mice compared with control mice (P < 0.05).The cellular inhibitor of apoptosis protein I (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. (C) 2017 European Federation of Immunological Societies. Published by Elsevier B.V. All rights reserved.
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