Walker D G, Whetzel A M, Lue L-F
Laboratory of Neuroinflammation, Banner Sun Health Research Institute, Sun City, AZ 85351, USA.
Laboratory of NeuroRegeneration, Banner Sun Health Research Institute, Sun City, AZ 85351, USA.
Neuroscience. 2015 Aug 27;302:121-37. doi: 10.1016/j.neuroscience.2014.09.052. Epub 2014 Oct 5.
Multiple cellular systems exist to prevent uncontrolled inflammation in brain tissues; the suppressor of cytokine signaling (SOCS) proteins have key roles in these processes. SOCS proteins are involved in restricting cellular signaling pathways by enhancing the degradation of activated receptors and removing the stimuli for continued activation. There are eight separate SOCS genes that code for proteins with similar structures and properties. All SOCS proteins can reduce signaling of activated transcription factors Janus kinase (JAK) and signal transducer and activator of transcription (STAT), but they also regulate many other signaling pathways. SOCS-1 and SOCS-3 have particular roles in regulating inflammatory processes. Chronic inflammation is a key feature of the pathology present in Alzheimer's disease (AD)-affected brains resulting from responses to amyloid plaques or neurofibrillary tangles, the pathological hallmarks of AD. The goal of this study was to examine SOCS gene expression in human non-demented (ND) and AD brains and in human brain-derived microglia to determine if AD-related pathology resulted in a deficit of these critical molecules. We demonstrated that SOCS-1, SOCS-2, SOCS-3 and cytokine-inducible SH2 containing protein (CIS) mRNA expression was increased in amyloid beta peptide (Aβ)- and inflammatory-stimulated microglia, while SOCS-6 mRNA expression was decreased by both types of treatments. Using human brain samples from the temporal cortex from ND and AD cases, SOCS-1 through SOCS-7 and CIS mRNA and SOCS-1 through SOCS-7 protein could be detected constitutively in ND and AD human brain samples. Although, the expression of key SOCS genes did not change to a large extent as a result of AD pathology, there were significantly increased levels of SOCS-2, SOCS-3 and CIS mRNA and increased protein levels of SOCS-4 and SOCS-7 in AD brains. In summary, there was no evidence of a deficit of these key inflammatory regulating proteins in aged or AD brains.
存在多种细胞系统来防止脑组织中炎症的失控；细胞因子信号转导抑制因子（SOCS）蛋白在这些过程中起关键作用。SOCS蛋白通过增强活化受体的降解并消除持续激活的刺激来参与限制细胞信号通路。有八个独立的SOCS基因，它们编码具有相似结构和特性的蛋白质。所有SOCS蛋白都可以减少活化转录因子 Janus激酶（JAK）和信号转导子及转录激活子（STAT）的信号传导，但它们也调节许多其他信号通路。SOCS-1和SOCS-3在调节炎症过程中具有特殊作用。慢性炎症是阿尔茨海默病（AD）患者大脑病理的一个关键特征，这是对淀粉样斑块或神经原纤维缠结（AD的病理标志）做出反应的结果。本研究的目的是检测人类非痴呆（ND）和AD大脑以及人脑来源的小胶质细胞中SOCS基因的表达，以确定AD相关病理是否导致这些关键分子的缺乏。我们证明，在淀粉样β肽（Aβ）和炎症刺激的小胶质细胞中，SOCS-1、SOCS-2、SOCS-3和细胞因子诱导的含SH2蛋白（CIS）的mRNA表达增加，而两种处理均使SOCS-6 mRNA表达降低。使用来自ND和AD病例颞叶皮质的人脑样本，在ND和AD人脑样本中可组成性地检测到SOCS-1至SOCS-7和CIS的mRNA以及SOCS-1至SOCS-7的蛋白。尽管AD病理导致关键SOCS基因的表达没有很大变化，但AD大脑中SOCS-2、SOCS-3和CIS的mRNA水平显著增加，SOCS-4和SOCS-7的蛋白水平增加。总之，没有证据表明在老年或AD大脑中这些关键的炎症调节蛋白存在缺乏。
