Tumor necrosis factor alpha triggers proliferation of adult neural stem cells via IKK/NF-kappaB signaling.
Tumor necrosis factor alpha triggers proliferation of adult neural stem cells via IKK/NF-kappaB signaling.
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肿瘤坏死因子α通过IKK/NF-kappab信号传导触发成年神经干细胞的增殖。
DOI：
10.1186/1471-2202-7-64
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发表时间：
2006-09-20
期刊：
影响因子：
2.4
通讯作者：
Kaltschmidt B
中科院分区：
文献类型：
--
作者：
Widera D;Mikenberg I;Elvers M;Kaltschmidt C;Kaltschmidt B
脑炎症已被认为是一种复杂的现象，有许多相关的方面。除了炎症的神经退行性作用，一些研究表明，炎症信号对神经干细胞增殖，迁移和分化产生潜在的积极影响。肿瘤坏死因子α（TNF-α）是最具特征的炎症介质之一。迄今为止，关于TNF对神经干细胞或祖细胞（NSCs，NPCs）的作用的结论一直相互矛盾。TNF似乎激活NSC增殖并抑制其分化为NPC。本研究的目的是分析TNF诱导NSC增殖的分子信号转导机制。在这里，我们首次描述了肿瘤坏死因子介导的信号转导级联神经干细胞（NSC），导致增殖增加。此外，我们证明了TNF处理后IKK-α/β依赖性增殖和显著上调的cyclin D1表达。在TNF处理的细胞增殖的显着增加，增加神经球体积，增加溴脱氧尿苷（BrdU）掺入和更高的总细胞数。此外，TNF强烈激活核因子-κ B（NF-κB），如报告基因测定和活性特异性抗体所测量。NF-κB超阻遏物Iκ B-AA 1的表达强烈抑制对照和TNF处理的NSC的增殖。IκB泛素连接酶活性的药理学阻断导致NF-κB活性和增殖的可比性降低。此外，通过siRNA敲低IKK-β基因产物导致NF-κB活性降低，细胞周期蛋白D1表达减弱，最终导致细胞增殖降低。相比之下，TGFβ激活的激酶1（TAK-1）对于TNF介导的和内源性增殖部分是不可或缺的。了解干细胞增殖对未来的再生和抗肿瘤医学至关重要。TNF介导的IKK-β活化导致NF-κB活化，随后是真正的靶基因细胞周期蛋白D1的上调。经典NF-κB通路的激活导致神经干细胞的增殖强烈增加。
Brain inflammation has been recognized as a complex phenomenon with numerous related aspects. In addition to the very well-described neurodegenerative effect of inflammation, several studies suggest that inflammatory signals exert a potentially positive influence on neural stem cell proliferation, migration and differentiation. Tumor necrosis factor alpha (TNF-α) is one of the best-characterized mediators of inflammation. To date, conclusions about the action of TNF on neural stem or progenitor cells (NSCs, NPCs) have been conflicting. TNF seems to activate NSC proliferation and to inhibit their differentiation into NPCs. The purpose of the present study was to analyze the molecular signal transduction mechanisms induced by TNF and resulting in NSC proliferation. Here we describe for the first time the TNF-mediated signal transduction cascade in neural stem cells (NSCs) that results in increased proliferation. Moreover, we demonstrate IKK-α/β-dependent proliferation and markedly up-regulated cyclin D1 expression after TNF treatment. The significant increase in proliferation in TNF-treated cells was indicated by increased neurosphere volume, increased bromodeoxyuridin (BrdU) incorporation and a higher total cell number. Furthermore, TNF strongly activated nuclear factor-kappa B (NF-κB) as measured by reporter gene assays and by an activity-specific antibody. Proliferation of control and TNF-treated NSCs was strongly inhibited by expression of the NF-κB super-repressor IκB-AA1. Pharmacological blockade of IκB ubiquitin ligase activity led to comparable decreases in NF-κB activity and proliferation. In addition, IKK-β gene product knock-down via siRNA led to diminished NF-κB activity, attenuated cyclin D1 expression and finally decreased proliferation. In contrast, TGFβ-activated kinase 1 (TAK-1) is partially dispensable for TNF-mediated and endogenous proliferation. Understanding stem cell proliferation is crucial for future regenerative and anti-tumor medicine. TNF-mediated activation of IKK-β resulted in activation of NF-κB and was followed by up-regulation of the bona-fide target gene cyclin D1. Activation of the canonical NF-κB pathway resulted in strongly increased proliferation of NSCs.
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影响因子：
16.2
作者：
CHENG, B;CHRISTAKOS, S;MATTSON, MP
通讯作者：
MATTSON, MP
DOI：
10.1073/pnas.182296499
发表时间：
2002-09-03
影响因子：
11.1
作者：
Jin, KL;Zhu, YH;Greenberg, DA
通讯作者：
Greenberg, DA
影响因子：
20.1
作者：
Mehrhof, FB;Schmidt-Ullrich, R;Scheidereit, C
通讯作者：
Scheidereit, C
影响因子：
4.8
作者：
Ferguson, KL;Callaghan, SM;Slack, RS
通讯作者：
Slack, RS
DOI：
10.1016/j.devbrainres.2004.10.010
发表时间：
2005-01-01
期刊：
DEVELOPMENTAL BRAIN RESEARCH
影响因子：
--
作者：
Denis-Donini, S;Caprini, A;Grilli, M
通讯作者：
Grilli, M