β Cell-Specific Deletion of the IL-1 Receptor Antagonist Impairs β Cell Proliferation and Insulin Secretion
β Cell-Specific Deletion of the IL-1 Receptor Antagonist Impairs β Cell Proliferation and Insulin Secretion
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DOI：
10.1016/j.celrep.2018.01.063
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发表时间：
2018-02-13
期刊：
影响因子：
8.8
通讯作者：
Donath, Marc Y.
中科院分区：
文献类型：
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作者：
Boni-Schnetzler, Marianne;Hauselmann, Stephanie P.;Donath, Marc Y.
白细胞介素-1受体拮抗剂（IL-1 Ra）在肥胖和2型糖尿病（T2 D）期间在循环中升高，但在T2 D患者的胰岛中降低。在胰岛β细胞（β IL-1 Ra）特异性与骨髓细胞（myeloIL-1 Ra）特异性IL-1 Ra敲除（KO）小鼠中研究了局部IL-1 Ra的保护作用。β细胞中IL-1 Ra的缺失导致胰岛IL-1 Ra表达减少，但骨髓细胞中没有。骨髓细胞不是肥胖患者循环IL-1 Ra的主要来源。β IL-1 Ra基因敲除小鼠胰岛素分泌受损，B细胞增殖减少，胰岛增殖基因表达减少，沿着葡萄糖耐量受损。关键细胞周期调节因子E2 F1部分逆转了IL-1 β介导的对钾通道Kir6.2表达的抑制，并挽救了IL-1 Ra敲除胰岛中受损的胰岛素分泌。我们的研究结果为β细胞衍生的IL-1 Ra对于B细胞的局部防御以维持正常功能和增殖的重要性提供了证据。
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 beta cell (beta IL-1Ra)-specific versus myeloid-cell (myeloIL-1Ra)-specific IL-1Ra knockout (KO) mice. Deletion of IL-1Ra in beta 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. beta IL-1Ra KO mice had impaired insulin secretion, reduced b cell proliferation, and decreased expression of islet proliferation genes, along with impaired glucose tolerance. The key cell-cycle regulator E2F1 partly reversed IL-1 beta-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 beta cell-derived IL-1Ra for the local defense of b cells to maintain normal function and proliferation.