Huaxun Wu1, Hui Li2, Wen Wen2, Yongchao Wang3, Hong Xu4, Mei Xu4, Jacqueline A Frank4, Wei Wei1, Jia Luo2. 1. Institute of Clinical Pharmacology, Key Laboratory of Anti-inflammatory and Immune Medicine, Ministry of Education, Anhui Medical University, Hefei, China. 2. Department of Pathology, University of Iowa Carver College of Medicine, Iowa City, IA, USA. 3. Department of Cell and Development Biology, Vanderbilt University School of Medicine, Nashville, TN, USA. 4. Department of Pharmacology and Nutritional Sciences, University of Kentucky College of Medicine, Lexington, KY, USA.
Abstract
BACKGROUND/ PURPOSE: Heavy alcohol drinking is associated with pancreatitis. Pancreatitis is initiated by the damage to the pancreatic acinar cells. The endoplasmic reticulum (ER) stress has been shown to play an important role in alcohol-induced pancreatic damage. Mesencephalic astrocyte-derived neurotrophic factor (MANF) is an ER stress-inducible protein. The aim of the study was to determine whether MANF can ameliorate alcohol-induced ER stress and cellular damages to pancreatic acinar cells. METHODS: Alcohol-induced damage to mouse pancreatic 266-6 acinar cells was determined by MTT and flow cytometry. MANF expression was downregulated by MANF siRNA using the Neon Transfection System. The overexpression of MANF was performed by the infection with the adenoviral vector carrying mouse MANF gene. The expression of ER stress markers was determined by immunoblotting and immunofluorescence. RESULTS: Alcohol caused ER stress, oxidative stress and induced apoptosis of 266-6 acinar cells. Recombinant human MANF alleviated alcohol-induced ER stress and cell death by inhibiting IRE1-caspase 12-caspase 3 apoptotic pathway. Overexpression of mouse MANF also protected cells against alcohol-induced apoptosis. In contrast, inhibiting MANF by siRNA exacerbated alcohol-induced cellular damage. CONCLUSIONS: MANF was protective against alcohol-induced ER stress and cellular injury in pancreatic acinar cells. The findings suggest a potential therapeutic value of MANF for alcoholic pancreatitis.
BACKGROUND/ PURPOSE: Heavy alcohol drinking is associated with pancreatitis. Pancreatitis is initiated by the damage to the pancreatic acinar cells. The endoplasmic reticulum (ER) stress has been shown to play an important role in alcohol-induced pancreatic damage. Mesencephalic astrocyte-derived neurotrophic factor (MANF) is an ER stress-inducible protein. The aim of the study was to determine whether MANF can ameliorate alcohol-induced ER stress and cellular damages to pancreatic acinar cells. METHODS: Alcohol-induced damage to mouse pancreatic 266-6 acinar cells was determined by MTT and flow cytometry. MANF expression was downregulated by MANF siRNA using the Neon Transfection System. The overexpression of MANF was performed by the infection with the adenoviral vector carrying mouse MANF gene. The expression of ER stress markers was determined by immunoblotting and immunofluorescence. RESULTS: Alcohol caused ER stress, oxidative stress and induced apoptosis of 266-6 acinar cells. Recombinant human MANF alleviated alcohol-induced ER stress and cell death by inhibiting IRE1-caspase 12-caspase 3 apoptotic pathway. Overexpression of mouse MANF also protected cells against alcohol-induced apoptosis. In contrast, inhibiting MANF by siRNA exacerbated alcohol-induced cellular damage. CONCLUSIONS: MANF was protective against alcohol-induced ER stress and cellular injury in pancreatic acinar cells. The findings suggest a potential therapeutic value of MANF for alcoholic pancreatitis.
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