Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Denmark.
Translational Science, Cardiovascular, Renal and Metabolism, IMED Biotech Unit, AstraZeneca, Gothenburg, Sweden.
Mol Cell Endocrinol. 2018 Dec 15;478:106-114. doi: 10.1016/j.mce.2018.08.001. Epub 2018 Aug 16.
β-Cells may be a source of IL-1β that is produced as inactive pro-IL-1β and processed into biologically-active IL-1β by enzymatic cleavage mediated by the NLRP1-, NLRP3- and NLRC4-inflammasomes. Little is known about the β-cell inflammasomes. NLRP1-expression was upregulated in islet-cells from T2D-patients and by IL-1β+IFNγ in INS-1 cells in a histone-deacetylase dependent manner. NLRP3 was downregulated by cytokines in INS-1 cells. NLRC4 was barely expressed and not regulated by cytokines. High extracellular K reduced cytokine-induced apoptosis and NO production and restored cytokine-inhibited accumulated insulin-secretion. Basal inflammasome expression was JNK1-3 dependent. Knock-down of the ASC interaction domain common for NLRP1 and 3 improved insulin secretion and ameliorated IL-1β and/or glucolipotoxicity-induced cell death and reduced cytokine-induced NO-production. Broad inflammasome-inhibition, but not NLRP3-selective inhibition, protected against IL-1β-induced INS-1 cell-toxicity. We suggest that IL-1β causes β-cell toxicity in part by NLRP1 mediated caspase-1-activation and maturation of IL-1β leading to an autocrine potentiation loop.
β 细胞可能是白细胞介素 1β（IL-1β）的来源，IL-1β 以前体形式（无活性的 pro-IL-1β）合成，并通过 NLRP1、NLRP3 和 NLRC4 炎性小体介导的酶切作用加工成具有生物活性的 IL-1β。关于 β 细胞炎性小体知之甚少。NLRP1 在 T2D 患者的胰岛细胞中以及在 INS-1 细胞中由 IL-1β+IFNγ 以组蛋白去乙酰化酶依赖性方式上调表达。NLRP3 在 INS-1 细胞中受细胞因子下调。NLRC4 表达水平较低，不受细胞因子调节。高细胞外 K 可减少细胞因子诱导的细胞凋亡和 NO 生成，并恢复细胞因子抑制的胰岛素分泌。基础炎性小体表达依赖于 JNK1-3。敲低 NLRP1 和 3 共有的 ASC 相互作用域可改善胰岛素分泌，并改善 IL-1β 和/或糖脂毒性诱导的细胞死亡，减少细胞因子诱导的 NO 生成。广谱炎性小体抑制，而非 NLRP3 选择性抑制，可预防 IL-1β 诱导的 INS-1 细胞毒性。我们认为，IL-1β 引起 β 细胞毒性的部分原因是 NLRP1 介导的半胱天冬酶-1 激活和 IL-1β 的成熟，导致自分泌增强环。
