Astrocyte TLR4 Activation Induces a Proinflammatory Environment Through the Interplay Between MyD88-Dependent NFκB Signaling, MAPK, and Jak1/Stat1 Pathways
Astrocyte TLR4 Activation Induces a Proinflammatory Environment Through the Interplay Between MyD88-Dependent NFκB Signaling, MAPK, and Jak1/Stat1 Pathways
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DOI：
10.1002/glia.21094
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发表时间：
2011-02-01
期刊：
影响因子：
6.2
通讯作者：
Planas, Anna M.
中科院分区：
文献类型：
--
作者：
Gorina, Roser;Font-Nieves, Miriam;Planas, Anna M.
越来越多的证据表明，星形胶质细胞在脑内的免疫调节中发挥重要作用。星形胶质细胞表达Toll样受体（TLR），并通过释放促炎分子建立对先天免疫触发剂的反应。我们研究了星形胶质细胞TLR 4激活后的信号通路和释放的分子。用TLR 4激活剂细菌脂多糖（LPS）处理纯化的啮齿动物脑星形胶质细胞培养物。用于干扰该系统的工具包括小干扰RNA、抑制性药物和MyD 88或Stat 1缺陷小鼠。LPS通过MyD 88接头诱导转录因子NF κ B的早期活化，以及TNF-α、VCAM-1、IL-15和IL-27的表达。LPS还诱导延迟的Jak 1/Stat 1激活，这是MyD 88不依赖的，但不是由IFN-β介导的。Jak 1/Stat 1激活诱导负性细胞因子调节因子SOCS-1和CXCL 10趋化因子（IP-10）的表达。丝裂原活化蛋白激酶（MAPK）也以MyD 88非依赖性方式参与TLR 4信号传导。p38通过调节Stat 1的磷酸化和NF κ B B的转录活性对LPS诱导的基因表达产生强烈影响，JNK调节Jak 1/Stat 1通路，ERK 1/2控制Egr-1的表达并影响MyD 88依赖的MMP-9的表达。这些信号之间的相互作用被证明是增加诱导MMP-9在Stat 1缺陷细胞与LPS的挑战，表明Stat 1负调控LPS诱导的MMP-9的表达。因此，星形胶质细胞通过诱导由NF κ B B、MAPK和Jak 1/Stat 1信号通路介导的一组复杂的细胞依赖性分子反应来响应TLR 4活化。在这里，我们确定了产生促炎环境的串扰信号，该促炎环境将调节周围细胞的反应。(C)2010 Wiley-Liss，Inc.
There is increasing evidence that astrocytes play important roles in immune regulation in the brain. Astrocytes express toll-like receptors (TLR) and build up responses to innate immune triggers by releasing proinflammatory molecules. We investigate signaling pathways and released molecules after astrocyte TLR4 activation. Purified rodent brain astrocyte cultures were treated with the TLR4 activator bacterial lipopolysaccharide (LPS). Tools used to interfere with this system include small interference RNA, inhibitory drugs, and MyD88 or Stat1 deficient mice. LPS induced early activation of the transcription factor NF kappa B, through the MyD88 adaptor, and expression of TNF-alpha, VCAM-1, IL-15, and IL-27. LPS also induced delayed Jak1/Stat1 activation, which was MyD88-independent but was not mediated by IFN-beta. Jak1/Stat1 activation induced the expression of negative cytokine regulator SOCS-1 and CXCL10 chemokine (IP-10). Mitogen-activated protein kinases (MAPK) were also involved in TLR4 signaling in a MyD88-independent fashion. p38 exerted a strong influence on LPS-induced gene expression by regulating the phosphorylation of Stat1 and the transcriptional activity of NF kappa B, while JNK regulated the Jak1/Stat1 pathway, and ERK1/2 controlled the expression of Egr-1 and influenced MyD88-dependent MMP-9 expression. Interplay between these signals was evidenced by the increased induction of MMP-9 in Stat1-deficient cells challenged with LPS, suggesting that Stat1 negatively regulates the expression of MMP-9 induced by LPS. Therefore, astrocytes are responsive to TLR4 activation by inducing a complex set of cell-dependent molecular reactions mediated by NF kappa B, MAPK and Jak1/Stat1 signaling pathways. Here we identified cross-talking signals generating a proinflammatory environment that will modulate the response of surrounding cells. (C) 2010 Wiley-Liss, Inc.