Department of Endocrinology, Diabetes, and Metabolism, University Hospital Basel, 4031 Basel, Switzerland; Department of Biomedicine, University of Basel, 4031 Basel, Switzerland.
Department of Endocrinology, Diabetes, and Metabolism, University Hospital Basel, 4031 Basel, Switzerland; Department of Biomedicine, University of Basel, 4031 Basel, Switzerland.
Cell Rep. 2018 Feb 13;22(7):1774-1786. doi: 10.1016/j.celrep.2018.01.063.
Interleukin-1 receptor antagonist (IL-1Ra) is elevated in the circulation during obesity and type 2 diabetes (T2D) but is decreased in islets from patients with T2D. The protective role of local IL-1Ra was investigated in pancreatic islet β cell (βIL-1Ra)-specific versus myeloid-cell (myeloIL-1Ra)-specific IL-1Ra knockout (KO) mice. Deletion of IL-1Ra in β cells, but not in myeloid cells, resulted in diminished islet IL-1Ra expression. Myeloid cells were not the main source of circulating IL-1Ra in obesity. βIL-1Ra KO mice had impaired insulin secretion, reduced β cell proliferation, and decreased expression of islet proliferation genes, along with impaired glucose tolerance. The key cell-cycle regulator E2F1 partly reversed IL-1β-mediated inhibition of potassium channel Kir6.2 expression and rescued impaired insulin secretion in IL-1Ra knockout islets. Our findings provide evidence for the importance of β cell-derived IL-1Ra for the local defense of β cells to maintain normal function and proliferation.
白细胞介素-1 受体拮抗剂 (IL-1Ra) 在肥胖症和 2 型糖尿病 (T2D) 患者的循环中升高，但在 T2D 患者的胰岛中降低。在胰腺胰岛β细胞（βIL-1Ra）特异性和髓样细胞（myeloIL-1Ra）特异性白细胞介素-1 受体拮抗剂 (IL-1Ra) 敲除 (KO) 小鼠中，研究了局部 IL-1Ra 的保护作用。β 细胞而非髓样细胞中 IL-1Ra 的缺失导致胰岛 IL-1Ra 表达减少。髓样细胞不是肥胖症中循环 IL-1Ra 的主要来源。βIL-1Ra KO 小鼠表现出胰岛素分泌受损、β 细胞增殖减少和胰岛增殖基因表达减少，同时糖耐量受损。细胞周期关键调节因子 E2F1 部分逆转了 IL-1β 介导的钾通道 Kir6.2 表达抑制，并挽救了 IL-1Ra 敲除胰岛中受损的胰岛素分泌。我们的研究结果为β 细胞来源的 IL-1Ra 对维持β 细胞正常功能和增殖的局部防御的重要性提供了证据。
