ICAM-1 Abundance Is Increased in Pancreatic Islets of Hyperglycemic Female NOD Mice and Is Rapidly Upregulated by NF-κB in Pancreatic β-Cells.
ICAM-1 Abundance Is Increased in Pancreatic Islets of Hyperglycemic Female NOD Mice and Is Rapidly Upregulated by NF-κB in Pancreatic β-Cells.
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DOI：
10.4049/jimmunol.2200065
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发表时间：
2022-08-01
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影响因子：
--
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1型糖尿病（T1D）被分类为自身免疫性疾病，其中胰腺β细胞被免疫系统的细胞特异性靶向。这一过程的分子机制尚未完全了解。在此，我们确定了Icam 1基因和ICAM-1蛋白在雌性NOD小鼠中相对于雄性小鼠选择性升高，这与T1D关键小鼠模型中糖尿病发作的性二态性相吻合。此外，高血糖雌性NOD小鼠中ICAM-1丰度高于年龄匹配的血糖正常雌性NOD小鼠。此外，我们发现小鼠、大鼠和人胰岛以及832/13大鼠胰岛素瘤细胞中的Icam 1基因在对IL-1 β的反应中迅速上调。这种早期的时间遗传调节需要NF-κ B通路的关键组分，并且与NF-κ B的p65转录亚基快速募集到Icam 1基因启动子内的相应κ B元件相关。此外，IL-1 β诱导的RNA聚合酶II向Icam 1基因启动子的募集与p65在κ B元件的占据、组蛋白化学修饰和mRNA丰度增加一致。因此，我们得出结论，β细胞通过IL-1 β进行快速遗传重编程，以增强ICAM-1基因的表达，并且ICAM-1的升高与NOD小鼠的高血糖症相关。这些发现与胰腺β细胞与免疫系统的通讯高度相关，并强调了其重要性。总的来说，这些观察结果揭示了与T1D发作和进展相关的复杂分子事件的一部分。
Type 1 diabetes (T1D) is classified as an autoimmune disease where pancreatic β-cells are specifically targeted by cells of the immune system. The molecular mechanisms underlying this process are not completely understood. Herein, we identified that the Icam1 gene and ICAM-1 protein were selectively elevated in female NOD mice relative to male mice, fitting with the sexual dimorphism of diabetes onset in this key mouse model of T1D. In addition, ICAM-1 abundance was greater in hyperglycemic female NOD mice compared with age-matched normoglycemic female NOD mice. Moreover, we discovered that the Icam1 gene was rapidly upregulated in response to IL-1β in mouse, rat, and human islets and in 832/13 rat insulinoma cells. This early temporal genetic regulation requires key components of the NF-κB pathway and was associated with rapid recruitment of the p65 transcriptional subunit of NF-κB to corresponding κB elements within the Icam1 gene promoter. In addition, RNA polymerase II recruitment to the Icam1 gene promoter in response to IL-1β was consistent with p65 occupancy at κB elements, histone chemical modifications, and increased mRNA abundance. Thus, we conclude that β-cells undergo rapid genetic reprogramming by IL-1β to enhance expression of the Icam1 gene and that elevations in ICAM-1 are associated with hyperglycemia in NOD mice. These findings are highly relevant to, and highlight the importance of, pancreatic β-cell communication with the immune system. Collectively, these observations reveal a portion of the complex molecular events associated with onset and progression of T1D.
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DOI：
10.1152/ajpendo.00347.2013
发表时间：
2014-01-01
影响因子：
5.1
作者：
Burke, Susan J.;Lu, Danhong;Collier, J. Jason
通讯作者：
Collier, J. Jason
影响因子：
4.4
作者：
HASEGAWA, Y;YOKONO, K;KASUGA, M
通讯作者：
KASUGA, M
影响因子：
64.8
作者：
Baggiolini, M
通讯作者：
Baggiolini, M
口服皮质酮可减少雄性非肥胖糖尿病小鼠的胰岛素抵抗，但会促进胰岛素抵抗和高血糖
影响因子：
6
作者：
Burke, Susan J.;Batdorf, Heidi M.;Collier, J. Jason
通讯作者：
Collier, J. Jason
影响因子：
4.8
作者：
Boeni-Schnetzler, Marianne;Boller, Simone;Donath, Marc Y.
通讯作者：
Donath, Marc Y.