Differential regulation of STAT family members by glycogen synthase kinase-3
Differential regulation of STAT family members by glycogen synthase kinase-3
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DOI：
10.1074/jbc.m802481200
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发表时间：
2008-08-08
影响因子：
4.8
通讯作者：
Jope, Richard S.
中科院分区：
文献类型：
--
作者：
Beurel, Eleonore;Jope, Richard S.
过度的神经炎症导致许多神经系统疾病，并且在治疗上控制不良。转录因子的信号转导子和转录激活子（STAT）家族在炎症反应中具有中心作用，其被多种细胞因子和干扰素刺激并调节参与炎症的许多蛋白质的表达。我们发现STAT 3的激活高度依赖于糖原合成酶激酶-3（GSK 3）。GSK 3抑制剂大大降低（> 75%）小鼠原代星形胶质细胞、小胶质细胞和巨噬细胞衍生的RAW264.7细胞中由干扰素-γ（IFN-γ）、IFN-α、白细胞介素-6或胰岛素诱导的激活性STAT 3酪氨酸磷酸化。GSK 3抑制剂阻断STAT 3 DNA结合活性和STAT 3诱导的GFAP和Bcl-3的表达。GSK 3依赖性对STAT 3和STAT 5的激活具有选择性，而STAT 1和STAT 6的激活则不依赖于GSK 3。两种GSK 3亚型的敲除显示STAT 3和STAT 5的激活依赖于GSK 3 β，而不是GSK 3 α。调节机制涉及GSK 3 β结合STAT 3并促进其与负责激活STAT 3的IFN γ受体相关的细胞内信号传导复合物的结合。此外，GSK 3 β与IFN γ受体相关，并通过IFN γ刺激激活。因此，GSK 3的抑制剂减少了STAT 3和STAT 5的活化，提供了差异调节STAT以调节炎症反应的机制。
Excessive neuroinflammation contributes to many neurological disorders and is poorly controlled therapeutically. The signal transducer and activator of transcription (STAT) family of transcription factors has a central role in inflammatory reactions, being stimulated by multiple cytokines and interferons and regulating the expression of many proteins involved in inflammation. We found that STAT3 activation is highly dependent on glycogen synthase kinase-3 (GSK3). Inhibitors of GSK3 greatly reduced (> 75%) the activating STAT3 tyrosine phosphorylation in mouse primary astrocytes, microglia, and macrophage-derived RAW264.7 cells induced by interferon-gamma (IFN gamma), IFN alpha, interleukin-6, or insulin. GSK3 inhibitors blocked STAT3 DNA binding activity and the expression of STAT3-induced GFAP and Bcl-3. GSK3 dependence was selective for activation of STAT3 and STAT5, whereas STAT1 and STAT6 activation were GSK3-independent. Knockdown of the two GSK3 isoforms showed STAT3 and STAT5 activation were dependent on GSK3 beta, but not GSK3 alpha. The regulatory mechanism involved GSK3 beta binding STAT3 and promoting its association with the IFN gamma receptor-associated intracellular signaling complex responsible for activating STAT3. Furthermore, GSK3 beta associated with the IFN gamma receptor and was activated by stimulation with IFN gamma. Thus, inhibitors of GSK3 reduce the activation of STAT3 and STAT5, providing a mechanism to differentially regulate STATs to modulate the inflammatory response.