期刊
HORMONE AND METABOLIC RESEARCH
卷 41, 期 3, 页码 207-212出版社
GEORG THIEME VERLAG KG
DOI: 10.1055/s-0028-1093343
关键词
type 1 diabetes; pancreatic beta cell; cytokine-induced apoptosis; Fast-induced apoptosis
资金
- German Research Foundation [AU 151/1-1, 1-2]
- German Academic Exchange Service (DAAD)
- German Federal Ministry of Education and Research [FKZ 0312711]
- Ministerium fur Bildung, Wissenschaft and Kultur Mecklenburg-Vorpommern [IDK 97 007 80/SOM, IDK 97 007 80/HSP III]
Cytokine- and FasL-induced pathways contribute to beta-cell death in type 1 diabetes. It remains unclear, however, whether pro-apoptotic cytokines or FasL have more apoptotic impact. Cytokine- and FasL-induced apoptosis were simulated using IL-1 beta/IFN-gamma, Super-FasLigand and the beta-cell line NIT-1. The role of caspases was addressed using the general caspase inhibitor ZVAD. Exposure to IL-1 beta/IFN-gamma induced NIT-1 cell death. FasL augmented cytokine-induced cell death accompanied by increased caspase-3 activation, DNA fragmentation, and chromatin condensation. However, FasL mediated comparable effects on the mitochondrial transmembrane potential (Delta psi(m)) and nitrite in cytokine- and untreated cells. The cytokine-induced sequence of apoptotic events was (1) Fas, nitrite, (2) Delta psi(m), (3) DNA fragmentation, cell death, and (4) chromatin condensation. In the presence of FasL, cell death and chromatin condensation appeared earlier implicating a compression of the apoptotic time course. General caspase inhibition using ZVAD prevented cell death, Delta psi(m), and DNA fragmentation; however, Fas expression and nitrite were increased. In conclusion, cytokines account for the major part of cell death induced by the simultaneously action of FasL + IL-1 beta/IFN-gamma. Caspases are of central importance for beta-cell death.
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