Induction of an inflammatory loop by interleukin-1β and tumor necrosis factor-α involves NF-kB and STAT-1 in differentiated human neuroprogenitor cells.
Induction of an inflammatory loop by interleukin-1β and tumor necrosis factor-α involves NF-kB and STAT-1 in differentiated human neuroprogenitor cells.
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DOI：
10.1371/journal.pone.0069585
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Mahaffey G
中科院分区：
文献类型：
--
作者：
Pugazhenthi S;Zhang Y;Bouchard R;Mahaffey G
已知由小胶质细胞分泌的促炎细胞因子可诱导星形胶质细胞的二次免疫反应，导致炎症循环。在衰老和神经退行性疾病中，细胞因子也会干扰神经发生。本研究从转录水平探讨了炎性介质在人分化神经前体细胞(NPC)中的诱导机制。免疫途径特异性芯片显示，白介素1β(IL 1β)和肿瘤坏死因子α(Tumor NectorFineα)可诱导分化的人NPC表达细胞因子和趋化因子。这些基因的网络基序(NM)分析显示118个三节点NMS，提示炎症介质和转录因子之间存在复杂的相互作用。免疫荧光染色显示神经元和神经胶质细胞中IL-8和CXCL10蛋白水平升高。塔克曼低密度阵列的研究结果表明，IL-1、β和肿瘤坏死因子-α通过一种涉及核因子-kB和STAT-1的机制，在诱导大多数炎症基因方面具有协同作用。在IL-1α和肿瘤坏死因子-α作用下，观察这些转录因子在分化的NPC中的核定位。对CXCL10的进一步研究表明，与IL-1α相比，肿瘤坏死因子-β对CXCL10启动子的诱导作用更强。当CXCL10启动子的ISRE或kB元件发生突变时，这些细胞因子之间的协同作用就会消失。我们的发现表明，神经元和星形胶质细胞中的炎症通路通过转录因子包括核因子-kB和STAT-1的激活，在神经胶质细胞的相互作用和维持炎症反应的恶性循环中发挥着重要作用。
Proinflammatory cytokines secreted from microglia are known to induce a secondary immune response in astrocytes leading to an inflammatory loop. Cytokines also interfere with neurogenesis during aging and in neurodegenerative diseases. The present study examined the mechanism of induction of inflammatory mediators at the transcriptional level in human differentiated neuroprogenitor cells (NPCs). Interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α) induced the expression of cytokines and chemokines in differentiated human NPCs as shown by an immune pathway-specific array. Network motif (NM) analysis of these genes revealed 118 three-node NMs, suggesting complex interactions between inflammatory mediators and transcription factors. Immunofluorescent staining showed increases in the levels of IL-8 and CXCL10 proteins in neurons and glial cells. Findings from Taqman low density array suggested the synergistic actions of IL-1β and TNF-α in the induction of a majority of inflammatory genes by a mechanism involving NF-kB and STAT-1. Nuclear localization of these transcription factors in differentiated NPCs was observed following exposure to IL-1α and TNF-α. Further studies on CXCL10, a chemokine known to be elevated in the Alzheimer's brain, showed that TNF-α is a stronger inducer of CXCL10 promoter when compared to IL-1β. The synergy between these cytokines was lost when ISRE or kB elements in CXCL10 promoter were mutated. Our findings suggest that the activation of inflammatory pathways in neurons and astrocytes through transcription factors including NF-kB and STAT-1 play important roles in neuroglial interactions and in sustaining the vicious cycle of inflammatory response.
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影响因子：
9.3
作者：
Nichol KE;Poon WW;Parachikova AI;Cribbs DH;Glabe CG;Cotman CW
通讯作者：
Cotman CW
DOI：
10.1016/j.bbrc.2012.01.130
发表时间：
2012-02-24
影响因子：
3.1
作者：
Hindlycke, Henrietta;Lu, Tao;Welsh, Nils
通讯作者：
Welsh, Nils
影响因子：
4.8
作者：
Moore, Fabrice;Naamane, Najib;Eizirik, Decio L.
通讯作者：
Eizirik, Decio L.
影响因子：
6
作者：
Janelsins, Michelle C.;Mastrangelo, Michael A.;Bowers, William J.
通讯作者：
Bowers, William J.
影响因子：
8.3
作者：
LIU, T;CLARK, RK;FEUERSTEIN, GZ
通讯作者：
FEUERSTEIN, GZ