title: Knockdown of GRP78 promotes apoptosis in pancreatic acinar cells and attenuates the severity of cerulein and LPS induced pancreatic inflammation.
abstract: Acute pancreatitis (AP) is a potentially lethal disease characterized by inflammation and parenchymal cell death; also, the severity of AP correlates directly with necrosis and inversely with apoptosis. However, mechanisms of regulating cell death in AP remain unclear. The endoplasmic reticulum (ER) chaperone protein GRP78 has anti-apoptotic properties, in addition to modulating ER stress responses. This study used RNA interference (RNAi) approach to investigate the potential role of GRP78 in regulating apoptosis during AP. In vitro models of AP were successfully developed by treating AR42J cells with cerulein or cerulein plus lipoplysaccharide (LPS). There was more pancreatic inflammation and less apoptosis with the cerulein plus LPS treatment. Furthermore, knockdown of GRP78 expression markedly promoted apoptosis and reduced necrosis in pancreatic acinar cells. This was accomplished by enhancing the activation of caspases and inhibiting the activity of X-linked inhibitor of apoptosis protein (XIAP), as well as a receptor interacting protein kinase-1(RIPK1), which is a key mediator of necrosis. This attenuated the severity of pancreatic inflammation, especially after cerulein plus LPS treatment. In conclusion, these findings indicate that GRP78 plays an anti-apoptotic role in regulating the cell death response during AP. Therefore, GRP78 is a potential therapeutic target for AP.
authors.affiliation: Department of Gastroenterological Surgery, West China Hospital, Sichuan University, Chengdu, Sichuan, China.
authors.forename: Yong
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Department of Gastroenterological Surgery, West China Hospital, Sichuan University, Chengdu, Sichuan, China.
authors.forename: Lie
authors.initials: L
authors.lastname: Yang
authors.affiliation: Institute of Digestive Surgery and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan, 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, Sichuan, China.
authors.forename: Bin
authors.initials: B
authors.lastname: Zhou
authors.affiliation: Department of Gastroenterological Surgery, West China Hospital, Sichuan University, Chengdu, Sichuan, China.
authors.forename: Hui
authors.initials: H
authors.lastname: Yan
authors.affiliation: Department of Gastroenterological Surgery, West China Hospital, Sichuan University, Chengdu, Sichuan, China; Institute of Digestive Surgery and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan, China.
authors.forename: Zong-Guang
authors.initials: ZG
authors.lastname: Zhou
authors.affiliation: Institute of Digestive Surgery and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan, China.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Li
mesh_terms: D061354:Acinar Cells / Q000502:physiology*; D000681:Amylases / Q000235:genetics / Q000378:metabolism; D000818:Animals; D017209:Apoptosis; D020169:Caspases / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D002108:Ceruletide / Q000494:pharmacology*; D016207:Cytokines / Q000378:metabolism; D015870:Gene Expression; D055785:Gene Knockdown Techniques; D006360:Heat-Shock Proteins / Q000235:genetics* / Q000378:metabolism; D008049:Lipase / Q000235:genetics / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology*; D046790:Pancreas, Exocrine / Q000276:immunology / Q000473:pathology*; D010195:Pancreatitis / Q000276:immunology*; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics; D051381:Rats; D015398:Signal Transduction; D000091342:Endoplasmic Reticulum Chaperone BiP
chemical_list: D000681:Amylases; D020169:Caspases; D002108:Ceruletide; D016207:Cytokines; D006360:Heat-Shock Proteins; D008049:Lipase; D008070:Lipopolysaccharides; D034741:RNA, Small Interfering; C051684:GRP78 protein, rat; D000091342:Endoplasmic Reticulum Chaperone BiP