Laboratory of Experimental Medicine, Université Libre de Bruxelles, Brussels, Belgium.
PLoS One. 2012;7(2):e31062. doi: 10.1371/journal.pone.0031062. Epub 2012 Feb 8.
In the course of Type 1 diabetes pro-inflammatory cytokines (e.g., IL-1β, IFN-γ and TNF-α) produced by islet-infiltrating immune cells modify expression of key gene networks in β-cells, leading to local inflammation and β-cell apoptosis. Most known cytokine-induced transcription factors have pro-apoptotic effects, and little is known regarding "protective" transcription factors. To this end, we presently evaluated the role of the transcription factor CCAAT/enhancer binding protein delta (C/EBPδ) on β-cell apoptosis and production of inflammatory mediators in the rat insulinoma INS-1E cells, in purified primary rat β-cells and in human islets. C/EBPδ is expressed and up-regulated in response to the cytokines IL-1β and IFN-γ in rat β-cells and human islets. Small interfering RNA-mediated C/EBPδ silencing exacerbated IL-1β+IFN-γ-induced caspase 9 and 3 cleavage and apoptosis in these cells. C/EBPδ deficiency increased the up-regulation of the transcription factor CHOP in response to cytokines, enhancing expression of the pro-apoptotic Bcl-2 family member BIM. Interfering with C/EBPδ and CHOP or C/EBPδ and BIM in double knockdown approaches abrogated the exacerbating effects of C/EBPδ deficiency on cytokine-induced β-cell apoptosis, while C/EBPδ overexpression inhibited BIM expression and partially protected β-cells against IL-1β+IFN-γ-induced apoptosis. Furthermore, C/EBPδ silencing boosted cytokine-induced production of the chemokines CXCL1, 9, 10 and CCL20 in β-cells by hampering IRF-1 up-regulation and increasing STAT1 activation in response to cytokines. These observations identify a novel function of C/EBPδ as a modulatory transcription factor that inhibits the pro-apoptotic and pro-inflammatory gene networks activated by cytokines in pancreatic β-cells.
在 1 型糖尿病中，浸润胰岛的免疫细胞产生的促炎细胞因子（如白细胞介素 1β、干扰素-γ 和肿瘤坏死因子-α）改变β细胞中关键基因网络的表达，导致局部炎症和β细胞凋亡。大多数已知的细胞因子诱导转录因子具有促凋亡作用，而关于“保护”转录因子的知识则知之甚少。为此，我们目前评估了转录因子 CCAAT/增强子结合蛋白δ（C/EBPδ）在大鼠胰岛素瘤 INS-1E 细胞、纯化的大鼠原代β细胞和人胰岛中对β细胞凋亡和炎症介质产生的作用。C/EBPδ 在大鼠β细胞和人胰岛中表达并响应细胞因子 IL-1β 和 IFN-γ 而上调。小干扰 RNA 介导的 C/EBPδ 沉默加剧了这些细胞中 IL-1β+IFN-γ 诱导的半胱天冬酶 9 和 3 的切割和凋亡。细胞因子反应中 C/EBPδ 缺失增加了转录因子 CHOP 的上调，增强了促凋亡 Bcl-2 家族成员 BIM 的表达。干扰 C/EBPδ 和 CHOP 或 C/EBPδ 和 BIM 的双敲除方法消除了 C/EBPδ 缺失对细胞因子诱导的β细胞凋亡的加剧作用，而 C/EBPδ 过表达抑制了 BIM 的表达，并部分保护β细胞免受 IL-1β+IFN-γ 诱导的凋亡。此外，C/EBPδ 沉默通过阻碍 IRF-1 的上调和增加细胞因子反应中的 STAT1 激活，促进了β细胞中细胞因子诱导的趋化因子 CXCL1、9、10 和 CCL20 的产生。这些观察结果确定了 C/EBPδ 作为一种调节转录因子的新功能，该转录因子抑制了细胞因子在胰腺β细胞中激活的促凋亡和促炎基因网络。
