A20 inhibits cytokine-induced apoptosis and nuclear factor kappaB-dependent gene activation in islets.
A20 inhibits cytokine-induced apoptosis and nuclear factor kappaB-dependent gene activation in islets.
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DOI：
10.1084/jem.190.8.1135
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发表时间：
1999-10-18
影响因子：
15.3
通讯作者：
Ferran, C
中科院分区：
文献类型：
--
作者：
Grey, S T;Arvelo, M B;Hasenkamp, W;Bach, F H;Ferran, C
胰岛素依赖型糖尿病（IDDM）是一种自身免疫性疾病，由胰岛中的 β 细胞凋亡破坏引起。抗氧化剂的低表达和倾向于产生一氧化氮 (NO) 已被证明会加剧 β 细胞凋亡。考虑到这一点，我们质疑 β 细胞是否能够对炎症产生诱导保护性反应。在这里，我们发现人类和大鼠的胰岛在白细胞介素（IL）-1β激活后可以被诱导快速表达抗凋亡基因A20。通过腺病毒介导的基因转移过度表达 A20 可保护胰岛免受 IL-1β 和干扰素 γ 诱导的细胞凋亡。 A20 对抗细胞凋亡的细胞保护作用与细胞因子诱导的 NO 产生的消除相关并依赖于细胞因子诱导的 NO 产生的消除。 A20 对细胞因子刺激的 NO 产生的抑制作用是由于诱导型 NO 合酶 (iNOS) 诱导的转录阻断； A20 在 IκBα 降解上游水平抑制转录因子核因子 κB 的激活。这些数据证明 A20 在 β 细胞中具有双重抗凋亡和抗炎功能。这使得 A20 成为胰岛生理细胞保护反应的一部分。我们认为 A20 可能具有作为基因治疗候选者的治疗潜力，以实现成功的胰岛移植和治愈 IDDM。
Insulin-dependent diabetes mellitus (IDDM) is an autoimmune disease resulting from apoptotic destruction of β cells in the islets of Langerhans. Low expression of antioxidants and a predilection to produce nitric oxide (NO) have been shown to underscore β cell apoptosis. With this perspective in mind, we questioned whether β cells could mount an induced protective response to inflammation. Here we show that human and rat islets can be induced to rapidly express the antiapoptotic gene A20 after interleukin (IL)-1β activation. Overexpression of A20 by means of adenovirus-mediated gene transfer protects islets from IL-1β and interferon γ–induced apoptosis. The cytoprotective effect of A20 against apoptosis correlates with and is dependent on the abrogation of cytokine-induced NO production. The inhibitory effect of A20 on cytokine-stimulated NO production is due to transcriptional blockade of inducible NO synthase (iNOS) induction; A20 inhibits the activation of the transcription factor nuclear factor κB at a level upstream of IκBα degradation. These data demonstrate a dual antiapoptotic and antiinflammatory function for A20 in β cells. This qualifies A20 as part of the physiological cytoprotective response of islets. We propose that A20 may have therapeutic potential as a gene therapy candidate to achieve successful islet transplantation and the cure of IDDM.