Department of Cell and Developmental Biology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil.
BMC Mol Cell Biol. 2023 Mar 28;24(1):11. doi: 10.1186/s12860-023-00476-3.
Type I Diabetes mellitus (T1D) is characterized by a specific destruction of β-cells by the immune system. During this process pro-inflammatory cytokines are released in the pancreatic islets and contribute for β-cells demise. Cytokine-induced iNOS activation, via NF-κB, is implicated in induction of β-cells death, which includes ER stress activation. Physical exercise has been used as an adjunct for better glycemic control in patients with T1D, since it is able to increase glucose uptake independent of insulin. Recently, it was observed that the release of IL-6 by skeletal muscle, during physical exercise, could prevent β-cells death induced by pro-inflammatory cytokines. However, the molecular mechanisms involved in this beneficial effect on β-cells are not yet completely elucidated. Our aim was to evaluate the effect of IL-6 on β-cells exposed to pro-inflammatory cytokines.
Pre-treatment with IL-6 sensitized INS-1E cells to cytokine-induced cell death, increasing cytokine-induced iNOS and Caspase-3 expression. Under these conditions, however, there was a decrease in cytokines-induced p-eIF2-α but not p-IRE1expression, proteins related to ER stress. To address if this prevention of adequate UPR response is involved in the increase in β-cells death markers induced by IL-6 pre-treatment, we used a chemical chaperone (TUDCA), which improves ER folding capacity. Use of TUDCA increased cytokines-induced Caspase-3 expression and Bax/Bcl-2 ratio in the presence of IL-6 pre-treatment. However, there is no modulation of p-eIF2-α expression by TUDCA in this condition, with increase of CHOP expression.
Treatment with IL-6 alone is not beneficial for β-cells, leading to increased cell death markers and impaired UPR activation. In addition, TUDCA has not been able to restore ER homeostasis or improve β-cells viability under this condition, suggesting that other mechanisms may be involved.
1 型糖尿病（T1D）的特征是免疫系统对β细胞的特异性破坏。在此过程中，炎症细胞因子在胰岛中释放，并有助于β细胞的死亡。细胞因子诱导的 iNOS 激活通过 NF-κB 参与诱导β细胞死亡，其中包括 ER 应激激活。运动已被用作 T1D 患者更好血糖控制的辅助手段，因为它能够在不依赖胰岛素的情况下增加葡萄糖摄取。最近，人们观察到，在运动过程中骨骼肌释放的 IL-6 可以防止促炎细胞因子诱导的β细胞死亡。然而，这种对β细胞有益影响的分子机制尚未完全阐明。我们的目的是评估 IL-6 对暴露于促炎细胞因子的β细胞的影响。
IL-6 预处理使 INS-1E 细胞对细胞因子诱导的细胞死亡敏感，增加了细胞因子诱导的 iNOS 和 Caspase-3 表达。然而，在这种情况下，细胞因子诱导的 p-eIF2-α 表达减少，但 p-IRE1 表达没有减少，这与 ER 应激有关。为了确定 IL-6 预处理引起的β细胞死亡标志物增加是否与适当的 UPR 反应的抑制有关，我们使用了一种化学伴侣（TUDCA），它可以改善 ER 的折叠能力。在 IL-6 预处理的情况下，使用 TUDCA 增加了细胞因子诱导的 Caspase-3 表达和 Bax/Bcl-2 比值。然而，在这种情况下，TUDCA 并没有调节 p-eIF2-α 的表达，而是增加了 CHOP 的表达。
单独使用 IL-6 对β细胞没有益处，导致细胞死亡标志物增加和 UPR 激活受损。此外，在这种情况下，TUDCA 未能恢复 ER 平衡或改善β细胞活力，这表明可能涉及其他机制。
