TGF-beta1 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-beta1 (TGF-beta1) is a multifunctional polypeptide that is related to the progression of chronic pancreatitis. However, the mechanism of beta-cell damage by TGF-beta1 is unknown. Treatment with TGF-beta1 enhanced internucleosomal DNA cleavage caused by exogenous hydrogen peroxide in a hamster pancreatic beta-cell line (HIT). TGF-beta1 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-beta1 suppressed mRNA expression as well as reduced the activities of catalase and GPx. The decrease in the catalase and GPx activities in TGF-beta1-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-beta1 through suppression of antioxidative enzymes may cause cellular damage and consequent apoptosis and induce pancreatitis or diabetes.
Islam
K N
KN
Department of Biochemistry, Osaka University Medical School, Yamadaoka, Suita, Japan.
Kayanoki
Y
Y
Kaneto
H
H
Suzuki
K
K
Asahi
M
M
Fujii
J
J
Taniguchi
N
N
D007516:Adenoma, Islet Cell / Q000378:metabolism / Q000473:pathology; D000818:Animals; D017209:Apoptosis; D002374:Catalase / Q000037:antagonists & inhibitors* / Q000235:genetics; D006224:Cricetinae; D004247:DNA / Q000378:metabolism; D005434:Flow Cytometry; D015870:Gene Expression; D005979:Glutathione Peroxidase / Q000037:antagonists & inhibitors* / Q000235:genetics; D006861:Hydrogen Peroxide / Q000494:pharmacology; D010084:Oxidation-Reduction; D010190:Pancreatic Neoplasms / Q000378:metabolism / Q000473:pathology; D010545:Peroxides / Q000032:analysis; D012333:RNA, Messenger / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
D010545:Peroxides; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; D016212:Transforming Growth Factor beta; D004247:DNA; D006861:Hydrogen Peroxide; D002374:Catalase; D005979:Glutathione Peroxidase