Inflammatory signaling and aryl hydrocarbon receptor mediate synergistic induction of interleukin 6 in MCF-7 cells
Inflammatory signaling and aryl hydrocarbon receptor mediate synergistic induction of interleukin 6 in MCF-7 cells
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DOI：
10.1158/0008-5472.can-07-6168
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发表时间：
2008-05-15
期刊：
影响因子：
11.2
通讯作者：
Perdew, Gary H.
中科院分区：
文献类型：
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作者：
Hollingshead, Brett D.;Beischlag, Timothy V.;Perdew, Gary H.
多效性细胞因子白细胞介素6（IL-6）参与免疫细胞稳态。此外，肿瘤细胞中的IL-6表达和信号传导已显示引发促肿瘤和抗肿瘤性质。关于IL-6信号转导如何转化为生物学应答，存在过多的机制知识。然而，对于在肿瘤细胞环境中控制IL-6表达的因素知之甚少。本文中呈现的研究显示，在MCF-7乳腺癌和ECC-1宫颈内癌细胞中，芳香烃受体（AHR）活性的刺激与IL-1 β或佛波醇12-肉豆蔻酸酯13-乙酸酯（PMA）处理组合，导致IL-6水平的显著协同诱导，超过在没有AHR活化的情况下所看到的。染色质免疫沉淀实验表明，IL-6 mRNA表达的调节发生在染色质水平，因为在IL-6启动子上观察到AHR存在，以响应用AHR配体处理。IL-6表达的协同诱导持续72小时，IL-6蛋白的积累达到单独IL-1 β处理的4.8倍。此外，原型AHR应答基因Cyp 1a 1的转录调节受到PMA和IL-1 β处理的负调控。RELA表达的沉默减轻了IL-1 β介导的AHR转录活性的抑制，而PMA介导的抑制得以维持。此外，小干扰RNA研究表明，AHR和RELA是协同诱导IL-6所必需的。本文的研究结果揭示了AHR作为选择性调节某些肿瘤细胞类型中IL-6表达的潜在治疗靶点。这些数据还表明了一种可能的以前未被认识到的AHR介导的肿瘤促进机制。
The pleiotropic cytokine interleukin 6 (IL-6) is involved in immune cell homeostasis. Additionally, IL-6 expression and signaling in tumor cells have been shown to elicit both protumor and antitumor properties. There is a plethora of mechanistic knowledge regarding how IL-6 signal transduction translates to biological responses. However, there is little understanding as to what factors control IL-6 expression within a tumor cell environment. The studies presented herein show that, in MCF-7 breast and ECC-1 endocervical cancer cells, the stimulation of aryl hydrocarbon receptor (AHR) activity, in combination with IL-1 beta or phorhol 12-myristate 13-acetate (PMA) treatment, results in a marked synergistic induction of IL-6 levels over what is seen without AHR activation. Chromatin immunoprecipitation experiments suggest that the regulation of IL-6 mRNA expression occurs at the chromatin level, as AHR presence on the IL-6 promoter was observed in response to treatment with AHR ligand. Synergistic induction of IL-6 expression was sustained for 72 hours, with accumulation of IL-6 protein reaching levels 4.8-fold above IL-1 beta treatment alone. In addition, transcriptional regulation of the prototypic AHR responsive gene Cyp1a1 was negatively regulated by PMA and IL-1 beta treatment. Silencing of RELA expression alleviated IL-1 beta-mediated repression of AHR transcriptional activity, whereas PMA-mediated repression was maintained. Additionally, small interfering RNA studies reveal that AHR and RELA are necessary for synergistic induction of IL-6. The findings presented here reveal the AHR as a potential therapeutic target for selective modulation of IL-6 expression in some tumor cell types. The data also suggest a possible previously unrecognized mechanism of AHR-mediated tumor promotion.