KSRP: a checkpoint for inflammatory cytokine production in astrocytes.
KSRP: a checkpoint for inflammatory cytokine production in astrocytes.
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DOI：
10.1002/glia.22396
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发表时间：
2012-11
期刊：
影响因子：
6.2
通讯作者：
King, Peter H.
中科院分区：
文献类型：
--
作者：
Li, Xuelin;Lin, Wei-Jye;Chen, Ching-Yi;Si, Ying;Zhang, Xiaowen;Lu, Liang;Suswam, Esther;Zheng, Lei;King, Peter H.
中枢神经系统(CNS)慢性炎症是许多神经退行性疾病和自身免疫性疾病的主要特征。星形胶质细胞作为一种免疫活性细胞，在中枢神经系统炎症中发挥着重要作用。它能表达多种细胞因子，如肿瘤坏死因子-α和白介素1-β(IL-1β)，这些细胞因子可直接或通过免疫细胞募集促进炎症反应。因此，检查站到位，以保持对细胞因子生产的严格控制。细胞因子mRNAs 3‘非翻译区的腺苷/尿苷酸富含元件(ARE)通过调节mRNA的稳定性和翻译效率而成为一个主要的检查点。在这里，我们检测了KH型剪接调节蛋白(KSRP)对原代星形胶质细胞细胞因子表达和旁分泌表型的影响。KSRP是一种RNA结合蛋白，通过ARE破坏mRNAs的稳定。我们确定了一个炎性介质网络，包括肿瘤坏死因子-α和IL-1β，它们在−/−小鼠星形胶质细胞中的表达在RNA水平上比小鼠对照组增加了2到4倍。在激活后，KSRP−/−星形胶质细胞产生的肿瘤坏死因子-α和IL-1β的水平比对照细胞高15倍或更多。Ksrp−/−星形胶质细胞条件培养液体外诱导细胞趋化和神经细胞死亡。令人惊讶的是，我们观察到只有一小部分信使核糖核酸靶标的半衰期延长，而且只有在选择性激活星形胶质细胞之后。荧光素酶报告研究表明，KSRP在转录和转录后水平调节细胞因子基因的表达。我们的结果概述了KSRP在调节促炎介质方面的关键作用，并对广泛的中枢神经系统炎症性和自身免疫性疾病具有意义。
Chronic inflammation in the central nervous system (CNS) is a central feature of many neurodegenerative and autoimmune diseases. As an immunologically competent cell, the astrocyte plays an important role in CNS inflammation. It is capable of expressing a number of cytokines such as tumor necrosis factor alpha (TNF-α) and interleukin-1 beta (IL-1β) that promote inflammation directly and through the recruitment of immune cells. Checkpoints are therefore in place to keep tight control over cytokine production. Adenylate/uridylate-rich elements (ARE) in the 3′ untranslated region of cytokine mRNAs serve as a major checkpoint by regulating mRNA stability and translational efficiency. Here, we examined the impact of KH-type splicing regulatory protein (KSRP), an RNA binding protein which destabilizes mRNAs via the ARE, on cytokine expression and paracrine phenotypes of primary astrocytes. We identified a network of inflammatory mediators, including TNF-α and IL-1β, whose expression increased 2 to 4-fold at the RNA level in astrocytes isolated from KSRP−/− mice compared to littermate controls. Upon activation, KSRP−/− astrocytes produced TNF-α and IL-1β at levels that exceeded control cells by 15-fold or more. Conditioned media from KSRP−/− astrocytes induced chemotaxis and neuronal cell death in vitro. Surprisingly, we observed a prolongation of half-life in only a subset of mRNA targets and only after selective astrocyte activation. Luciferase reporter studies indicated that KSRP regulates cytokine gene expression at both transcriptional and post-transcriptional levels. Our results outline a critical role for KSRP in regulating pro-inflammatory mediators and have implications for a wide range of CNS inflammatory and autoimmune diseases.
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DOI：
10.1016/j.bbrc.2006.05.093
发表时间：
2006-07-21
影响因子：
3.1
作者：
Chen, Yu-Ling;Huang, Ya-Lin;Chang, Ching-Jin
通讯作者：
Chang, Ching-Jin
影响因子：
5.5
作者：
Aoki, Naoko;Kimura, Yuka;Tateno, Masatoshi
通讯作者：
Tateno, Masatoshi
影响因子：
5.3
作者：
Chung, Hye-Jung;Liu, Juhong;Levens, David
通讯作者：
Levens, David
影响因子：
64.8
作者：
Chen, Szu-Ting;Lin, Yi-Ling;Hsieh, Shie-Liang
通讯作者：
Hsieh, Shie-Liang
影响因子：
64.8
作者：
Bouchon, A;Facchetti, F;Colonna, M
通讯作者：
Colonna, M