Calcineurin/Nuclear Factor of Activated T Cells and MAPK Signaling Induce TNF-α Gene Expression in Pancreatic Islet Endocrine Cells
Calcineurin/Nuclear Factor of Activated T Cells and MAPK Signaling Induce TNF-α Gene Expression in Pancreatic Islet Endocrine Cells
复制标题
DOI：
10.1074/jbc.m110.158675
复制
发表时间：
2011-01-14
影响因子：
4.8
通讯作者：
Mcglynn, Kathleen
中科院分区：
文献类型：
--
作者：
Lawrence, Michael C.;Naziruddin, Bashoo;Mcglynn, Kathleen
细胞因子促进胰岛炎症，导致葡萄糖稳态受损和糖尿病疾病。大量的数据表明，促炎细胞因子通过浸润单核免疫细胞在胰岛中产生。在这里，我们表明，胰岛α细胞和β细胞表达肿瘤坏死因子-α（TNF-α）和其他细胞因子能够促进胰岛炎症时，暴露于白细胞介素-1 β（IL-1 β）。β细胞的细胞因子表达依赖于钙调神经磷酸酶（CN）/活化T细胞核因子（NFAT）和MAPK信号传导。NFAT与TNF-α启动子相关，对刺激有反应，并与ATF 2和c-Jun协同激活启动子活性。相反，当C/EBP-β与启动子结合时，β细胞特异性转录激活因子MafA可以抑制NFAT介导的TNF-α基因表达。NFAT根据β细胞中相互作用的碱性亮氨酸拉链伴侣的表达和MAPK依赖性激活差异调节TNF-α基因。p38和JNK都是诱导TNF-α mRNA和蛋白表达所必需的。总的来说，这些数据表明，葡萄糖和IL-1 β可以激活信号通路，控制胰腺内分泌细胞中细胞因子的诱导和抑制。因此，通过这些机制，胰腺β细胞本身可能会导致糖尿病发病机制中的胰岛炎症和自身免疫破坏。
Cytokines contribute to pancreatic islet inflammation, leading to impaired glucose homeostasis and diabetic diseases. A plethora of data shows that proinflammatory cytokines are produced in pancreatic islets by infiltrating mononuclear immune cells. Here, we show that pancreatic islet alpha cells and beta cells express tumor necrosis factor-alpha (TNF-alpha) and other cytokines capable of promoting islet inflammation when exposed to interleukin-1 beta (IL-1 beta). Cytokine expression by beta cells was dependent on calcineurin (CN)/nuclear factor of activated T cells (NFAT) and MAPK signaling. NFAT associated with the TNF-alpha promoter in response to stimuli and synergistically activated promoter activity with ATF2 and c-Jun. In contrast, the beta-cell-specific transcriptional activator MafA could repress NFAT-mediated TNF-alpha gene expression whenever C/EBP-beta was bound to the promoter. NFAT differentially regulated the TNF-alpha gene depending upon the expression and MAPK-dependent activation of interacting basic leucine zipper partners in beta cells. Both p38 and JNK were required for induction of TNF-alpha mRNA and protein expression. Collectively, the data show that glucose and IL-1 beta can activate signaling pathways, which control induction and repression of cytokines in pancreatic endocrine cells. Thus, by these mechanisms, pancreatic beta cells themselves may contribute to islet inflammation and their own immunological destruction in the pathogenesis of diabetes.