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Deletion Of XIAP reduces the severity of acute pancreatitis via regulation of cell death and nuclear factor-κB activity.

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机构： [1]Institute of Digestive Surgery and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China, [2]Department of Gastroenterological Surgery, West China Hospital, Sichuan University, Chengdu, China, [3]Department of General Surgery, Shanghai First People's Hospital, Shanghai Jiaotong University, Shanghai, China [4]Department of Oncology, Department of Clinical and Experiment Medicine, Linkoping University, Link?ping, Sweden

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Severe acute pancreatitis (SAP) still remains a clinical challenge, not only for its high mortality but the uncontrolled inflammatory progression from acute pancreatitis (AP) to SAP. Cell death, including apoptosis and necrosis are critical pathology of AP, since the severity of pancreatitis correlates directly with necrosis and inversely with apoptosis Therefore, regulation of cell death from necrosis to apoptosis may have practicably therapeutic value. X-linked inhibitor of apoptosis protein (XIAP) is the best characterized member of the inhibitor of apoptosis proteins (IAP) family, but its function in AP remains unclear. In the present study, we investigated the potential role of XIAP in regulation of cell death and inflammation during acute pancreatitis. The in vivo pancreatitis model was induced by the administration of cerulein with or without lipopolysaccharide (LPS) or by the administration of l-arginine in wild-type or XIAP-deficient mice, and ex vivo model was induced by the administration of cerulein+LPS in AR42J cell line following XIAP inhibition. The severity of acute pancreatitis was determined by serum amylase activity and histological grading. XIAP deletion on cell apoptosis, necrosis and inflammatory response were examined. Caspases activities, nuclear factor-κB (NF-κB) activation and receptor-interacting protein kinase1 (RIP1) degradation were assessed by western blot. Deletion of XIAP resulted in the reduction of amylase activity, decrease of NF-κB activation and less release of TNF-α and IL-6, together with increased caspases activities and RIP1 degradation, leading to enhanced apoptosis and reduced necrosis in pancreatic acinar cells and ameliorated the severity of acute pancreatitis. Our results indicate that deletion of XIAP switches cell death away from necrosis to apoptosis and decreases the inflammatory response, effectively attenuating the severity of AP/SAP. The critical role of XIAP in cell death and inflammation suggests that inhibition of XIAP represents a potential therapeutic strategy for the treatment of acute pancreatitis.

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出版当年[2017]版：

大类 | 2 区生物

小类 | 3 区细胞生物学

最新[2023]版：

大类 | 1 区

生物学

小类 | 2 区细胞生物学

第一作者：

第一作者机构： [1]Institute of Digestive Surgery and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China, [2]Department of Gastroenterological Surgery, West China Hospital, Sichuan University, Chengdu, China,

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通讯作者：

通讯机构： [1]Institute of Digestive Surgery and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China, [2]Department of Gastroenterological Surgery, West China Hospital, Sichuan University, Chengdu, China, [*1]Institute of Digestive Surgery and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, No.1 Ke-Yuan-Si- Lu, Gao-Peng-Da-Dao, Chengdu, Sichuan 610041, China

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