Peroxiredoxin III protects pancreatic ß cells from apoptosis.
Type 1 diabetes mellitus is characterized by a progressive autoimmune destruction of insulin-producing β cells. Macrophages and T lymphocytes release cytokines, which induce the synthesis of oxygen and nitrogen radicals in the pancreatic islets. The resulting cellular and mitochondrial damage promotes β cell death. β cells are very sensitive to the autoimmune free radical-dependent attack due to their low content of antioxidant enzymes such as glutathione peroxidase and catalase. A focal point of β cell protection should be the control of the mitochondrial redox status, which will result in the preservation of metabolic stimulus-secretion coupling. For this reason, there is a considerable interest in the mitochondrial peroxiredoxin III (PRX III), a thioredoxin-dependent peroxide reductase, which was shown to be able to protect against both oxidative and nitrosative stress. Using the Tet-On-system, we generated stably transfected rat insulinoma cells over- or under-expressing PRX III in a doxycyclin-dependent manner to analyze the effect of increased or decreased amounts of cellular PRX III, following treatment with several stressors. We provide evidence that PRX III protects pancreatic β cells from cell stress induced by accumulation of hydrogen peroxide, or the induction of inducible nitric oxide synthase or caspase-9 and -3 by pro-inflammatory cytokines or streptozotocin. Basal insulin secretion was markedly decreased in cells expressing lower levels of PRX III. We suggest PRX III may be a suitable target for promoting deceleration or even prevention of stress-associated apoptosis in pancreatic β cells and the manifestation of insulin-dependent diabetes mellitus.
Wolf
Gabriele
G
Department of Medical Biochemistry and Molecular Biology, University of Greifswald, Klinikum, Sauerbruchstrasse, D-17487 Greifswald, Germany.
Aumann
Nicole
N
Michalska
Marta
M
Bast
Antje
A
Sonnemann
Jürgen
J
Beck
James F
JF
Lendeckel
Uwe
U
Newsholme
Philip
P
Walther
Reinhard
R
D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D053148:Caspase 3 / Q000378:metabolism; D053453:Caspase 9 / Q000378:metabolism; D002460:Cell Line; D016207:Cytokines; D005260:Female; D005786:Gene Expression Regulation / Q000502:physiology*; D006861:Hydrogen Peroxide / Q000378:metabolism; D050417:Insulin-Secreting Cells / Q000502:physiology*; D007340:Insulinoma; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D010179:Pancreas / Q000378:metabolism; D054464:Peroxiredoxins / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D013311:Streptozocin
D016207:Cytokines; D013311:Streptozocin; D006861:Hydrogen Peroxide; D054464:Peroxiredoxins; D052247:Nitric Oxide Synthase Type II; D053148:Caspase 3; D053453:Caspase 9