Key Laboratory of Molecular Epigenetics of the Ministry of Education (MOE), School of Life Sciences, Northeast Normal University, Changchun, 130024, China.
HIT Center for Life Sciences, School of Life Science and Technology, Harbin Institute of Technology, Harbin 150080, China.
Theranostics. 2018 Nov 13;8(21):5960-5971. doi: 10.7150/thno.28960. eCollection 2018.
Islet α-cell dysfunction has been shown to contribute to type 2 diabetes; however, whether islet α-cell inflammation is involved in the occurrence of pancreatitis is largely unknown. The aims of this study were to investigate how NF-κB inducing kinase (NIK) regulates pancreatic α-cell function, both and , and to assess how islet α-cell inflammation induced by NIK affects the development of pancreatitis. We utilized adenovirus-mediated NIK overexpression, ELISA, qPCR, RNA-seq, and Western blot analyses to study the role of NIK in islet α cells . Islet α-cell-specific NIK overexpressing (α-NIK-OE) mice were generated, and pancreatic α/β-cell function and the occurrence of pancreatitis in these mice were assessed ELISA, qPCR, and immunohistochemical analyses. The LTβR/noncanonical NF-κB signaling pathway is present in islet α cells. Overexpression of NIK in αTC1-6 cells induces inflammation and cell death, contributing to a decrease in the expression and secretion of glucagon. Additionally, α-cell specific overexpression of NIK (α-NIK-OE) results in α-cell death, lower serum glucagon levels, and hypoglycemia in mice. Strikingly, α-NIK-OE mice also display a reduced β-cell mass, growth retardation, pancreatitis, and postnatal death. Islet α-cell specific overexpression of NIK results in islet α-cell dysfunction and causes islet β-cell death and pancreatitis, which are most likely due to paracrine secretion of cytokines and chemokines from islet α cells, thus leading to hypoglycemia, growth retardation, and postnatal death in mice.
胰岛 α 细胞功能障碍已被证明与 2 型糖尿病有关；然而，胰岛 α 细胞炎症是否参与胰腺炎的发生在很大程度上尚不清楚。本研究旨在探讨 NF-κB 诱导激酶 (NIK) 如何调节胰岛 α 细胞的功能，以及评估 NIK 诱导的胰岛 α 细胞炎症如何影响胰腺炎的发展。我们利用腺病毒介导的 NIK 过表达、ELISA、qPCR、RNA-seq 和 Western blot 分析来研究 NIK 在胰岛 α 细胞中的作用。生成了胰岛 α 细胞特异性 NIK 过表达（α-NIK-OE）小鼠，并评估了这些小鼠的胰腺 α/β 细胞功能和胰腺炎的发生。ELISA、qPCR 和免疫组织化学分析。LTβR/非经典 NF-κB 信号通路存在于胰岛 α 细胞中。在 αTC1-6 细胞中过表达 NIK 会诱导炎症和细胞死亡，导致胰高血糖素的表达和分泌减少。此外，α-NIK-OE 小鼠的胰岛 α 细胞特异性过表达导致胰岛 α 细胞死亡、血清胰高血糖素水平降低和低血糖。引人注目的是，α-NIK-OE 小鼠还表现出 β 细胞质量减少、生长迟缓、胰腺炎和出生后死亡。胰岛 α 细胞特异性过表达 NIK 导致胰岛 α 细胞功能障碍，并导致胰岛 β 细胞死亡和胰腺炎，这很可能是由于胰岛 α 细胞分泌的细胞因子和趋化因子的旁分泌作用，从而导致小鼠低血糖、生长迟缓和出生后死亡。
