PDF(Pubmed)
Abstract：
In type 1 diabetes (T1D), autoreactive immune cells infiltrate the pancreas and secrete proinflammatory cytokines that initiate cell death in insulin producing islet β-cells. Protein kinase C δ (PKCδ) plays a role in mediating cytokine-induced β-cell death; however, the exact mechanisms are not well understood. To address this, we used an inducible β-cell specific PKCδ KO mouse as well as a small peptide inhibitor of PKCδ. We identified a role for PKCδ in mediating cytokine-induced β-cell death and have shown that inhibiting PKCδ protects pancreatic β-cells from cytokine-induced apoptosis in both mouse and human islets. We determined that cytokines induced nuclear translocation and activity of PKCδ and that caspase-3 cleavage of PKCδ may be required for cytokine-mediated islet apoptosis. Further, cytokine activated PKCδ increases activity both of proapoptotic Bax with acute treatment and C-Jun N-terminal kinase with prolonged treatment. Overall, our results suggest that PKCδ mediates cytokine-induced apoptosis via nuclear translocation, cleavage by caspase-3, and upregulation of proapoptotic signaling in pancreatic β-cells. Combined with the protective effects of PKCδ inhibition with δV1-1, the results of this study will aid in the development of novel therapies to prevent or delay β-cell death and preserve β-cell function in T1D.
摘要：
在1型糖尿病（T1D）中，自身反应性免疫细胞浸润胰腺并分泌促炎细胞因子，从而引发产生胰岛素的胰岛β细胞的细胞死亡。蛋白激酶Cδ（PKCδ）在介导细胞因子诱导的β细胞死亡中起作用；然而，确切的机制还没有很好的理解。为了解决这个问题，我们使用了诱导型β细胞特异性PKCδKO小鼠以及PKCδ的小肽抑制剂。我们确定了PKCδ在介导细胞因子诱导的β细胞死亡中的作用，并表明抑制PKCδ可保护胰腺β细胞免受小鼠和人胰岛中细胞因子诱导的凋亡。我们确定细胞因子诱导了PKCδ的核易位和活性，并且细胞因子介导的胰岛细胞凋亡可能需要caspase-3裂解PKCδ。Further,细胞因子激活的PKCδ增加急性治疗的促凋亡Bax和长期治疗的JNK的活性。总的来说,我们的结果表明，PKCδ通过核转位介导细胞因子诱导的细胞凋亡，caspase-3的裂解，以及胰腺β细胞中促凋亡信号的上调。结合PKCδ抑制与δV1-1的保护作用，这项研究的结果将有助于开发新疗法，以预防或延迟β细胞死亡并保留T1D中的β细胞功能。
