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Current Trends in Endocrinology   Volumes    Volume 3 
Cytokine- and FasL-induced β-cell death in type 1 diabetes
Petra Augstein, Eckhard Salzsieder, Peter Heinke, Hans-Christof Schober, Leonard C. Harrison
Pages: 31 - 55
Number of pages: 25
Current Trends in Endocrinology
Volume 3 

Copyright © 2008 Research Trends. All rights reserved

Type 1 diabetes results from autoimmune destruction of the insulin-producing β cells in the islets of the pancreas. To determine whether β cells contribute to their own death, we investigated the mechanism of β-cell death in the autoimmune non-obese diabetic (NOD) mouse model of type 1 diabetes. Here, we provide a retrospective of this work. We also established models of cytokine- and FasL-induced apoptosis of β-cells in vitro. We monitored the time course of apoptotic parameters and investigated caspase 3-like activity. Finally, we investigated whether mouse islets and the NIT-1 β-cell line could resist FasL-induced β-cell death by down-regulating Fas. In NOD mice, islets with apoptosis were characterised by a reduced insulin-positive area, indicating ongoing β-cell destruction. In vitro, cytokines IL-1β/IFN-g induced death of NIT-1 cells and islet cells. Fas receptor expression was the earliest apoptotic parameter; FasL augmented cytokine-induced cell death. Impairment of mitochondrial inner transmembrane potential (DYm) and nitrite generation were effected by cytokines but not FasL. Cytokines induced Fas in NOD mouse islets and NIT-1 cells in a time- and dose-dependent manner. In the presence of FasL, Fas expression was reduced in NIT-1 cells but unaffected in islet cells. The general caspase inhibitor Z-VAD prevented cytokine- and FasL- induced NIT-1 cell death. Cytokine exposure resulted in increased caspase 3-like activity, which was augmented by FasL. In summary, destructive insulitis triggers apoptosis of β cells implying that interruption of apoptotic pathways could prevent autoimmune diabetes. In vitro, cytokines effect NIT-1 cell death directly, and indirectly by induction of Fas receptor. Both pathways of β-cell death result in activation of caspase 3. However, the degree of caspase 3-like activity was low in NIT-1 cells and NOD mouse islets compared with thymocytes. Whether activated caspase-3 has a pro-apoptotic or an alternate pro-survival role needs to be revealed in future studies. In contrast to primary islets cells, NIT-1 cells down-regulated Fas expression in response to ligation. While Fas receptor downregulation may be a particular feature of transformed cells such as NIT-1 cells; it nevertheless represents a potential strategy for protecting β cells from apoptotic cell death.
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