Suppressor of cytokine signaling 3 (SOCS-3) protects β-cells against interleukin-1β- and interferon-γ-mediated toxicity
Suppressor of cytokine signaling 3 (SOCS-3) protects β-cells against interleukin-1β- and interferon-γ-mediated toxicity
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DOI：
10.1073/pnas.211445998
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发表时间：
2001-10-09
影响因子：
11.1
通讯作者：
Billestrup, N
中科院分区：
文献类型：
--
作者：
Karlsen, AE;Ronn, SG;Billestrup, N
细胞因子信号传导抑制剂 3 (SOCS-3) 是 IFN-γ 信号传导的负反馈调节剂，在小鼠骨髓细胞中显示促炎细胞因子白介素-1β (IL-1β)、肿瘤坏死因子-α (TNF-α) 和 IFN-γ 上调。单独的 IL-1 β 和 IFN-γ 或经 TNF-α 增强后，在体外对产生胰岛素的胰腺 β 细胞和 β 细胞系具有细胞毒性，并被认为有助于 1 型糖尿病 (T1DM) 中特定的 β 细胞破坏。在大鼠 β 细胞系 INS-1 中使用多西环素诱导型 SOCS-3 表达系统，我们证明，当细胞中开启 SOCS-3 表达时，IL-1 β 或 IFN-γ 在 3 天内使存活率降低 50% 的浓度的毒性作用是完全可以预防的。在对细胞毒性更大的细胞因子浓度或组合下，SOCS-3 过度表达产生了部分保护。虽然在其他细胞系统中描述了 SOCS-3 介导的 IFN-γ 信号传导抑制，但之前尚未描述过 SOCS-3 介导的 IL-1 β 信号传导抑制。此外，我们还表明，SOCS-3 预防 IL-1 β 诱导的毒性伴随着诱导型一氧化氮合酶 (iNOS) 转录抑制 80%，导致有毒一氧化氮 (NO) 的形成减少 60%。对暴露于 IL-1 beta 的分离的天然大鼠胰岛的分析揭示了自然发生但延迟的 SOCS-3 转录上调。因此，影响 SOCS-3 表达代表了一种在信号级联中近端影响细胞因子诱导的信号转导的方法，可能可用于未来旨在降低 T1DM 以及其他细胞因子依赖性疾病中 β 细胞细胞毒性细胞因子的破坏潜力的治疗。
Suppressor of cytokine signaling 3 (SOCS-3) is a negative feedback regulator of IFN-gamma signaling, shown up-regulated in mouse bone marrow cells by the proinflammatory cytokines interleukin-1 beta (IL-1 beta), tumor necrosis factor-alpha (TNF-alpha), and IFN-gamma. IL-1 beta and IFN-gamma alone, or potentiated by TNF-alpha, are cytotoxic to the insulin producing pancreatic beta -cells and beta -cell lines in vitro and suggested to contribute to the specific beta -cell destruction in Type-1 diabetes mellitus (T1DM). Using a doxycycline-inducible SOCS-3 expression system in the rat beta -cell line INS-1, we demonstrate that the toxic effect of both IL-1 beta or IFN-gamma at concentrations that reduced the viability by 50% over 3 days, was fully preventable when SOCS-3 expression was turned on in the cells. At cytokine concentrations or combinations more toxic to the cells, SOCS-3 overexpression yielded a partial protection. Whereas SOCS-3-mediated inhibition of IFN-gamma signaling is described in other cell systems, SOCS-3 mediated inhibition of IL-1 beta signaling has not previously been described. In addition we show that SOCS-3 prevention of IL-1 beta -induced toxicity is accompanied by inhibited transcription of the inducible nitric oxide synthase (iNOS) by 80%, resulting in 60% decreased formation of the toxic nitric oxide (NO). Analysis of isolated native rat islets exposed to IL-1 beta revealed a naturally occurring but delayed up-regulated SOCS-3 transcription. Influencing SOCS-3 expression thus represents an approach for affecting cytokine-induced signal transduction at a proximal step in the signal cascade, potentially useful in future therapies aimed at reducing the destructive potential of beta -cell cytotoxic cytokines in T1DM, as well as other cytokine-dependent diseases.