Regulation of signal transducer and activator of transcription and suppressor of cytokine-signaling gene expression in the brain of mice with astrocyte-targeted production of interleukin-12 or experimental autoimmune encephalomyelitis
Regulation of signal transducer and activator of transcription and suppressor of cytokine-signaling gene expression in the brain of mice with astrocyte-targeted production of interleukin-12 or experimental autoimmune encephalomyelitis
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DOI：
10.1016/s0002-9440(10)64371-4
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发表时间：
2002-01-01
影响因子：
6
通讯作者：
Campbell, IL
中科院分区：
文献类型：
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作者：
Maier, J;Kincaid, C;Campbell, IL
白细胞介素（IL）-12和干扰素（IFN）-γ参与中枢神经系统（CNS）免疫疾病的发病机制。为了确定这些细胞因子在中枢神经系统中作用的基础，我们研究了关键信号转导子和转录激活子（STAT）和细胞因子信号转导抑制子（SOCS）在星形胶质细胞产生IL-12的转基因小鼠或实验性自身免疫性脑脊髓炎（EAE）小鼠脑中的时空调节。在健康小鼠中，除了STAT 4和STAT 6，许多STAT和SOCS基因的表达是可检测的。然而，在有症状的转基因小鼠和EAE中，观察到STAT 1、STAT 2、STAT 3、STAT 4、IRF 9和SOCS 1和SOCS 3 RNA转录物显著上调。尽管STAT 1 RNA的表达增加广泛分布，包括神经元、星形胶质细胞和小胶质细胞，但STAT 4和STAT 3以及SOCS 1和SOCS 3 RNA主要限于浸润的单核细胞群。STAT 1、STAT 3和STAT 4蛋白的水平和位置与其相应的RNA重叠，并且另外显示了指示这些分子活化的核定位。因此，在神经胶质细胞酸性蛋白-IL-12小鼠和EAE中，调节IL-12（STAT 4）和IFN-γ（STAT 1、SOCK和SOCS 3）受体信号传导的关键STAT和SOCS基因的CNS表达被高度调节和区室化。我们得出结论，这些积极和消极的信号电路和它们的不同的细胞位置之间的相互作用可能发挥了决定性的作用，在协调的行动，IL-12和IFN-γ在中枢神经系统的1型免疫反应的发病机制。
Interleukin (IL)-12 and interferon (IFN)-gamma are implicated in the pathogenesis of immune disorders of the central nervous system (CNS). To define the basis for the actions of these cytokines in the CNS, we examined the temporal and spatial regulation of key signal transducers and activators of transcription (STATs) and suppressors of cytokine signaling (SOCS) in the brain of transgenic mice with astrocyte production of IL-12 or in mice with experimental autoimmune encephalomyelitis (EAE). In healthy mice, with the exception of STAT4 and STAT6, the expression of a number of STAT and SOCS genes was detectable. However, in symptomatic transgenic mice and in EAE significant up-regulation of STAT1, STAT2, STAT3, STAT4, IRF9, and SOCS1 and SOCS3 RNA transcripts was observed. Although the increased expression of STAT1 RNA was widely distributed and Included neurons, astrocytes, and microglia, STAT4 and STAT3 and SOCS1 and SOCS3 RNA was primarily restricted to the infiltrating mononuclear cell population. The level and location of the STAT1, STAT3, and STAT4 proteins overlapped with their corresponding RNA and additionally showed nuclear localization indicative of activation of these molecules. Thus, in both the glial fibrillary acidic protein-IL-12 mice and In EAE the CNS expression of key STAT and SOCS genes that regulate IL-12 (STAT4) and IFN-gamma (STAT 1, SOCK, and SOCS3) receptor signaling is highly regulated and compartmentalized. We conclude the interaction between these positive and negative signaling circuits and their distinct cellular locations likely play a defining role in coordinating the actions of IL-12 and IFN-gamma during the pathogenesis of type 1 immune responses in the CNS.