Cytokine-induced human islet cell death in vitro correlates with a persistently high phosphorylation of STAT-1, but not with NF-魏B activation

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• 作者：Henrietta Hindlycke^a ; Tao Lu^b ; Nils Welsh^a ; ^{nils.welsh@mcb.uu.se}
• 关键词：Human islets ; Apoptosis ; NF-魏B ; STAT-1 ; Cytokines ; Nitric oxide
• 刊名：Biochemical and Biophysical Research Communications
• 出版年：2012
• 期刊代码：159_0006291x
• 类别：bio
• 出版时间：24 February, 2012
• 卷：418
• 期：4
• 页码：845-850
• 文件大小：532 K

摘要

Studies of insulin producing 尾-cells have reported conflicting responses to NF-魏B activation, encompassing both pro- and anti-apoptotic effects, possibly reflecting the use of 尾-cells from different species. Therefore, the aim of this study was to compare the temporal activation of NF-魏B in rat and human insulin producing cells and relate this to the dynamics of cell death, STAT-1 activation and the production of nitric oxide (NO). Rat RIN5AH and human islet cells were exposed to the cytokines IL-1尾 and IFN-纬 and the NOS inhibitor aminoguanidine. Cell death, NO production, I魏B伪 phosphorylation, p65 methylation, STAT-1 phosphorylation and cIAP-2 levels were analyzed at different time-points. Cytokine-induced RIN5AH cell death occurred on day 1, and this was paralleled by NF-魏B activation, STAT-1 phosphorylation and production of NO. On the other hand, the human islet cells instead died by an NO-independent mechanism on day 3 and 5. This later occurring cell death was associated with a gradual decrease in I魏B伪 phosphorylation and p65 methylation, and a lowered expression of the NF-魏B target genes I魏B伪 and cIAP-2. STAT-1 phosphorylation was persistently high during the entire cytokine exposure period in human islet cells. The results favor a pro-survival role of NF-魏B and a pro-apoptotic role of STAT-1 in human islet cells. Thus, rodent insulin producing cells may not be suitable as models for human 尾-cells in the context of cytokine-induced damage.