TGF-β1 Triggers Oxidative Modifications and Enhances Apoptosis in Hit Cells Through Accumulation of Reactive Oxygen Species by Suppression of Catalase and Glutathione Peroxidase

Transforming growth factor-β1 (TGF-β1) is a multifunctional polypeptide that is related to the progression of chronic pancreatitis. However, the mechanism of β-cell damage by TGF-β1 is unknown. Treatment with TGF-β1 enhanced internucleosomal DNA cleavage caused by exogenous hydrogen peroxide in a hamster pancreatic β-cell line (HIT). TGF-β1 also induced protein oxidation, assessed by measuring carbonyl groups in proteins, and was involved in reactions that lead to lipid peroxidation. This eventually destructs membrane lipids and forms malondialdehyde. We have investigated its effects on two major antioxidative enzymes, catalase and glutathione peroxidase (GPx). TGF-β1 suppressed mRNA expression as well as reduced the activities of catalase and GPx. The decrease in the catalase and GPx activities in TGF-β1-treated cells resulted in an increase in intracellular peroxides as judged by flow cytometric analysis using a peroxide-sensitive dye, 2′,7′-dichlorofluorescin diacetate. These data suggest that the augmented production of reactive oxygen species by TGF-β1 through suppression of antioxidative enzymes may cause cellular damage and consequent apoptosis and induce pancreatitis or diabetes. Copyright © 1997 Elsevier Science Inc.