title: Reg4 protects against acinar cell necrosis in experimental pancreatitis.
abstract: Background and aims Reg4 is a recently discovered member of the regenerating gene family with distinctive expression profiles in primary cancers. To date, the physiological function of Reg4 is poorly understood. Previously, the authors found that Reg4 was markedly upregulated during acute pancreatitis (AP). The aim of this study was to investigate the role of Reg4 in experimental pancreatitis. Methods AP was induced in C57BL/6 mice by administration of either l-arginine or caerulein, and Reg4 expression was assessed by immunofluorescence, reverse transcriptase (RT)-PCR and western blot analyses. Recombinant human Reg4 protein (rReg4), heat-inactivated Reg4, neutralising antibody and vehicle were also administered to mice by subcutaneous injection. The severity of AP was determined by measuring amylase and lipase activities in the serum and histological grading. The effect of rReg4 on cell death was examined and epidermal growth factor receptor (EGFR), p-EGFR, Akt, p-Akt, Bcl-2 and Bcl-xL expression were assessed by western blot analysis of isolated murine acinar cells treated with l-arginine. Results Reg4 mRNA and protein were markedly upregulated during arginine-induced pancreatitis. Reg4 was widely expressed in residual acinar cells around the islets and regenerating metaplastic epithelium. rReg4 could protect against arginine-induced necrosis of acinar cells both in vivo and in vitro. This protective effect was also confirmed in the caerulein-induced murine model of AP. It was shown that arginine induced expression of Bcl-2 and Bcl-xL, while rReg4 upregulated Bcl-2 and Bcl-xL expression by activating the EGFR/Akt pathway. The upregulation of Bcl-xL correlated inversely with cell necrosis in isolated pancreatic acinar cells. Conclusions The data suggest that Reg4 may protect against acinar cell necrosis in experimental pancreatitis by enhancing the expression of Bcl-2 and Bcl-xL via activation of the EGFR/Akt signalling pathway.
authors.affiliation: Department of Gastroenterology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, 200072, China.
authors.forename: Guoyong
authors.initials: G
authors.lastname: Hu
authors.forename: Jiaqing
authors.initials: J
authors.lastname: Shen
authors.forename: Li
authors.initials: L
authors.lastname: Cheng
authors.forename: Chuanyong
authors.initials: C
authors.lastname: Guo
authors.forename: Xuanfu
authors.initials: X
authors.lastname: Xu
authors.forename: Feng
authors.initials: F
authors.lastname: Wang
authors.forename: Li
authors.initials: L
authors.lastname: Huang
authors.forename: Lijuan
authors.initials: L
authors.lastname: Yang
authors.forename: Miao
authors.initials: M
authors.lastname: He
authors.forename: Di
authors.initials: D
authors.lastname: Xiang
authors.forename: Shunying
authors.initials: S
authors.lastname: Zhu
authors.forename: Mingyuan
authors.initials: M
authors.lastname: Wu
authors.forename: Yan
authors.initials: Y
authors.lastname: Yu
authors.forename: Wei
authors.initials: W
authors.lastname: Han
authors.forename: Xingpeng
authors.initials: X
authors.lastname: Wang
mesh_terms: D000818:Animals; D001120:Arginine / Q000494:pharmacology; D016923:Cell Death / Q000187:drug effects; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical / Q000379:methods; D066246:ErbB Receptors / Q000378:metabolism; D037181:Lectins, C-Type / Q000627:therapeutic use; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology; D010179:Pancreas / Q000473:pathology; D019283:Pancreatitis, Acute Necrotizing / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D000073718:Pancreatitis-Associated Proteins; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis; D011994:Recombinant Proteins / Q000494:pharmacology / Q000627:therapeutic use*; D015854:Up-Regulation / Q000187:drug effects; D051020:bcl-X Protein / Q000096:biosynthesis
chemical_list: C494812:Bcl2l1 protein, mouse; D037181:Lectins, C-Type; D009363:Neoplasm Proteins; D000073718:Pancreatitis-Associated Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; C428528:REG4 protein, human; C546117:REG4 protein, mouse; D011994:Recombinant Proteins; D051020:bcl-X Protein; D001120:Arginine; D066246:ErbB Receptors; D051057:Proto-Oncogene Proteins c-akt