Dichotomy between Receptor-Interacting Protein 1- and Receptor-Interacting Protein 3-Mediated Necroptosis in Experimental Pancreatitis.
Pancreatic acinar cell necrosis and inflammatory responses are two key pathologic processes in acute pancreatitis (AP), which determines the severity and outcome of the disease. Recent studies suggest that necroptosis, a programed form of necrosis, is involved in the pathogenesis of AP, but the underlying mechanisms remain unknown. We investigated the expression of necrosome components, including receptor-interacting protein (RIP) 1, RIP3, and mixed lineage kinase domain-like (MLKL), and the molecular mechanisms in pancreatitis-associated necroptosis. We found that RIP3 and phosphorylated MLKL expression was positively related to the degree of necrosis, whereas RIP1 expression was negatively related to the degree of necrosis. Pharmacologic inhibition of RIP1 kinase activity exerted no protection against caerulein/cholecystokinin-8-induced AP, but knockdown of RIP1 with siRNA increased acinar cell necrosis and inhibition of NF-κB activation. RIP1 inhibition led to enhanced RIP3 expression. RIP3 and MLKL inhibition decreased acinar cell necrosis, in which the inhibition of RIP3 reduced the phosphorylation level of MLKL. RIP3 inhibition had no effect on trypsinogen activation but partly inhibited inflammasome activation. Our study strongly suggests that the imbalance between RIP1 and RIP3 shifts the cell death to necrosis, which unravels a new molecular pathogenesis of mechanism of AP and may provide insight into the development of novel therapeutic agent for other necrosis-related diseases.
Department of Gastroenterology and the Shanghai Key Laboratory of Pancreatic Disease, Shanghai General Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.
Jianghong
J
Wu
Department of Gastroenterology and the Shanghai Key Laboratory of Pancreatic Disease, Shanghai General Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.
Tunike
T
Mulatibieke
Department of Gastroenterology and the Shanghai Key Laboratory of Pancreatic Disease, Shanghai General Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.
Jianbo
J
Ni
Department of Gastroenterology and the Shanghai Key Laboratory of Pancreatic Disease, Shanghai General Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.
Xiao
X
Han
Department of Gastroenterology and the Shanghai Key Laboratory of Pancreatic Disease, Shanghai General Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.
Bin
B
Li
Department of Gastroenterology and the Shanghai Key Laboratory of Pancreatic Disease, Shanghai General Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.
Yue
Y
Zeng
Department of Gastroenterology and the Shanghai Key Laboratory of Pancreatic Disease, Shanghai General Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.
Rong
R
Wan
Department of Gastroenterology and the Shanghai Key Laboratory of Pancreatic Disease, Shanghai General Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China. Electronic address: richardwangxp@163.com.
Xingpeng
X
Wang
Department of Gastroenterology and the Shanghai Key Laboratory of Pancreatic Disease, Shanghai General Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China. Electronic address: huguoyongsh@sina.com.
Guoyong
G
Hu
D061354:Acinar Cells / Q000502:physiology; D000208:Acute Disease; D000818:Animals; D017209:Apoptosis / Q000502:physiology; D002108:Ceruletide / Q000633:toxicity; D002766:Cholecystokinin / Q000633:toxicity; D007509:Irritants / Q000633:toxicity; D008297:Male; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D009336:Necrosis / Q000503:physiopathology; D010195:Pancreatitis / Q000473:pathology*; D010446:Peptide Fragments / Q000633:toxicity; D010766:Phosphorylation / Q000502:physiology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D017207:Rats, Sprague-Dawley; D053422:Receptor-Interacting Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology*
D007509:Irritants; D010446:Peptide Fragments; D047428:Protein Kinase Inhibitors; C410885:cholecystokinin 8; D002108:Ceruletide; D002766:Cholecystokinin; C506249:RIPK1 protein, human; C119705:RIPK3 protein, human; D053422:Receptor-Interacting Protein Serine-Threonine Kinases