Journal Article

Reg4 protects against acinar cell necrosis in experimental pancreatitis

Xu, Xuanfu, Huang, Li, Wu, Mingyuan, Guo, Chuanyong, Cheng, Li, Yang, Lijuan, Hu, Guoyong, Wang, Feng, Han, Wei, Xiang, Di, Zhu, Shunying, Wang, Xingpeng, Yu, Yan, Shen, Jiaqing, He, Miao

2011

Overview

Background and aimsReg4 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.MethodsAP 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.ResultsReg4 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.ConclusionsThe 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.

• Publisher: BMJ Publishing Group Ltd and British Society of Gastroenterology,BMJ Publishing Group,BMJ Publishing Group LTD
• Subject: Acinar cells / AKT protein / Animal models / Animals / Apoptosis / Arginine / Arginine - pharmacology / Bcl-2 / Bcl-2 protein / Bcl-x protein / bcl-X Protein - biosynthesis / Bcl-xl / Biological and medical sciences / Cell death / Cell Death - drug effects / Cell growth / Cells, Cultured / Cytokines / Disease / Disease Models, Animal / Dose-Response Relationship, Drug / Drug Evaluation, Preclinical - methods / Epidermal growth factor receptors / Epithelium / family proteins / Gangrene / Gastroenterology. Liver. Pancreas. Abdomen / Genes / Immunofluorescence / Inflammatory bowel disease / Laboratory animals / Lectins, C-Type - therapeutic use / Liver. Biliary tract. Portal circulation. Exocrine pancreas / Male / Medical sciences / Mice / Mice, Inbred C57BL / Necrosis / Neoplasm Proteins - biosynthesis / Neoplasm Proteins - genetics / Neoplasm Proteins - physiology / Other diseases. Semiology / Pancreas / Pancreas - pathology / Pancreatic cancer / pancreatic damage / pancreatic pathology / Pancreatitis / Pancreatitis, Acute Necrotizing - chemically induced / Pancreatitis, Acute Necrotizing - metabolism / Pancreatitis, Acute Necrotizing - pathology / Pancreatitis, Acute Necrotizing - prevention & control / Pancreatitis-Associated Proteins / Phosphorylation - drug effects / Physiology / Protein expression / Proteins / Proto-Oncogene Proteins c-akt - metabolism / Proto-Oncogene Proteins c-bcl-2 - biosynthesis / Receptor, Epidermal Growth Factor - metabolism / Recombinant Proteins - pharmacology / Recombinant Proteins - therapeutic use / Reg4 / RNA-directed DNA polymerase / Rodents / Signal transduction / Studies / Tumor necrosis factor-TNF / Up-Regulation - drug effects