title: Deletion Of XIAP reduces the severity of acute pancreatitis via regulation of cell death and nuclear factor-κB activity.
abstract: 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.
authors.affiliation: Institute of Digestive Surgery and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China.|Department of Gastroenterological Surgery, West China Hospital, Sichuan University, Chengdu, China.
authors.forename: Yong
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Institute of Digestive Surgery and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China.
authors.forename: Xiao-Dong
authors.initials: XD
authors.lastname: Chen
authors.affiliation: Institute of Digestive Surgery and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China.
authors.forename: Jiang
authors.initials: J
authors.lastname: Yu
authors.affiliation: Institute of Digestive Surgery and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China.
authors.forename: Jun-Lin
authors.initials: JL
authors.lastname: Chi
authors.affiliation: Institute of Digestive Surgery and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China.
authors.forename: Fei-Wu
authors.initials: FW
authors.lastname: Long
authors.affiliation: Institute of Digestive Surgery and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China.
authors.forename: Hong-Wei
authors.initials: HW
authors.lastname: Yang
authors.affiliation: Institute of Digestive Surgery and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China.
authors.forename: Ke-Ling
authors.initials: KL
authors.lastname: Chen
authors.affiliation: Institute of Digestive Surgery and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China.
authors.forename: Zhao-Ying
authors.initials: ZY
authors.lastname: Lv
authors.affiliation: Institute of Digestive Surgery and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China.
authors.forename: Bin
authors.initials: B
authors.lastname: Zhou
authors.affiliation: Department of General Surgery, Shanghai First People's Hospital, Shanghai Jiaotong University, Shanghai, China.
authors.forename: Zhi-Hai
authors.initials: ZH
authors.lastname: Peng
authors.affiliation: Institute of Digestive Surgery and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China.|Department of Oncology, Department of Clinical and Experiment Medicine, Linköping University, Linköping, Sweden.
authors.forename: Xiao-Feng
authors.initials: XF
authors.lastname: Sun
authors.affiliation: Institute of Digestive Surgery and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Li
authors.affiliation: Institute of Digestive Surgery and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China.|Department of Gastroenterological Surgery, West China Hospital, Sichuan University, Chengdu, China.
authors.forename: Zong-Guang
authors.initials: ZG
authors.lastname: Zhou
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D001120:Arginine / Q000378:metabolism; D020169:Caspases / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects / Q000502:physiology*; D002460:Cell Line; D002108:Ceruletide / Q000494:pharmacology; D007249:Inflammation / Q000378:metabolism; D051034:Inhibitor of Apoptosis Proteins / Q000378:metabolism*; D015850:Interleukin-6 / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000378:metabolism*; D009336:Necrosis / Q000378:metabolism / Q000473:pathology; D010179:Pancreas / Q000000981:diagnostic imaging / Q000378:metabolism; D010195:Pancreatitis / Q000378:metabolism* / Q000473:pathology*; D053422:Receptor-Interacting Protein Serine-Threonine Kinases / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D051636:X-Linked Inhibitor of Apoptosis Protein / Q000378:metabolism
chemical_list: C107521:Birc4 protein, mouse; D051034:Inhibitor of Apoptosis Proteins; D015850:Interleukin-6; D016328:NF-kappa B; D014409:Tumor Necrosis Factor-alpha; D051636:X-Linked Inhibitor of Apoptosis Protein; D002108:Ceruletide; D001120:Arginine; D053422:Receptor-Interacting Protein Serine-Threonine Kinases; D020169:Caspases