IFN-ε Mediates TNF-α-Induced STAT1 Phosphorylation and Induction of Retinoic Acid-Inducible Gene-I in Human Cervical Cancer Cells1
IFN-ε Mediates TNF-α-Induced STAT1 Phosphorylation and Induction of Retinoic Acid-Inducible Gene-I in Human Cervical Cancer Cells1
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IFN-ε 介导人宫颈癌细胞中 TNF-α 诱导的 STAT1 磷酸化和视黄酸诱导基因 I 的诱导1
作者：
T. Matsumiya;S. Prescott;D. Stafforini
视黄酸诱导基因-I(RIG-I)在病毒感染的先天免疫反应中发挥重要作用，并作为细胞因子信号转导因子。细胞因子刺激后RIG-I上调的机制尚不完全清楚。已有报道称干扰素-γ可诱导内皮细胞表达RIG-I。在这项研究中，我们研究了I型干扰素介导的RIG-I在HeLa细胞中上调的机制，发现除了I型干扰素外，调节先天免疫反应的细胞因子肿瘤坏死因子-α还诱导RIG-I的表达。为了研究肿瘤坏死因子-α-和I型干扰素介导的RIG-I上调是否存在因果关系，我们研究了这些反应的动力学。我们的结果与肿瘤坏死因子-α作用于I型IFN上游的模型是一致的。肿瘤坏死因子-α上调RIG-I的能力需要蛋白质合成、功能性I型IFNRs的表达和STAT1信号。我们还发现，干扰素-ε是唯一在HeLa细胞中组成性表达的干扰素亚型，并且其表达随着肿瘤坏死因子-α的刺激而上调。上调的机制包括在没有转录激活的情况下稳定干扰素-ε基因。沉默干扰素-ε的表达可减少STAT1的表达和磷酸化，并抑制RIG-I的表达，为干扰素-ε参与STAT1上游的表达提供了额外的支持。我们的发现支持一种序贯机制，即肿瘤坏死因子-α导致干扰素-ε基因的稳定，干扰素-ε的合成增加，I型IFNRs的参与，STAT1表达和磷酸化的增加，以及RIG-I表达的上调。这些发现对我们理解细胞因子刺激后的免疫反应具有重要意义。
Retinoic acid inducible gene-I (RIG-I) plays important roles during innate immune responses to viral infections and as a transducer of cytokine signaling. The mechanisms of RIG-I up-regulation after cytokine stimulation are incompletely characterized. It was previously reported that IFN–γ induces the expression of RIG-I in endothelial cells. In this study, we characterized the mechanism of type I IFN-mediated up-regulation of RIG-I in HeLa cells and found that, in addition to type I IFN, TNF-α, a cytokine that regulates innate immune responses, induced expression of RIG-I. To investigate whether TNF-α- and type I IFN-mediated up-regulations of RIG-I were causally related, we studied the kinetics of these responses. Our results were consistent with a model in which TNF-α functioned upstream of type I IFNs. The ability of TNF-α to up-regulate RIG-I required protein synthesis, expression of functional type I IFNRs, and STAT1 signaling. We also found that IFN-ε was the only IFN isoform expressed constitutively in HeLa cells and that its expression was up-regulated in response to stimulation with TNF-α. The mechanism of up-regulation involved stabilization of IFN-ε mRNA in the absence of transcriptional activation. Silencing the expression of IFN-ε attenuated STAT1 expression and phosphorylation and inhibited RIG-I expression, providing additional support for the participation of IFN-ε upstream of STAT1. Our findings support a sequential mechanism whereby TNF-α leads to stabilization of IFN-ε mRNA, increased IFN-ε synthesis, engagement of type I IFNRs, increased STAT1 expression and phosphorylation, and up-regulation of RIG-I expression. These findings have implications for our understanding of the immune responses that follow cytokine stimulation.
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影响因子：
4.4
作者：
S. Laster;J. G. Wood;L. Gooding
通讯作者：
S. Laster;J. G. Wood;L. Gooding
影响因子：
3.4
作者：
Quayle, AJ
通讯作者：
Quayle, AJ
DOI：
10.1006/bbrc.2002.6650
发表时间：
2002-03-22
影响因子：
3.1
作者：
Imaizumi, T;Aratani, S;Satoh, K
通讯作者：
Satoh, K
DOI：
10.1073/pnas.0601523103
发表时间：
2006-04-11
影响因子：
11.1
作者：
Loo, YM;Owen, DM;Gale, M
通讯作者：
Gale, M