Network analyses: Inhibition of androgen receptor signaling reduces inflammation in the lung through AR-MAF-IL6 signaling axes.
Network analyses: Inhibition of androgen receptor signaling reduces inflammation in the lung through AR-MAF-IL6 signaling axes.
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网络分析：抑制雄激素受体信号传导可通过 AR-MAF-IL6 信号传导轴减少肺部炎症。
DOI：
10.1016/j.gendis.2023.07.001
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发表时间：
2024-05
期刊：
影响因子：
6.8
通讯作者：
Iyer, Gopal
中科院分区：
文献类型：
--
作者：
Wang, Albert R.;Baschnagel, Andrew M.;Ni, Zijian;Brennan, Sean R.;Newton, Hypatia K.;Buehler, Darya;Kendziorski, Christina;Kimple, Randall J.;Iyer, Gopal
雄激素受体（AR）是一种主要的转录因子，在炎症反应中起作用，包括白细胞介素-6（IL-6）信号传导。虽然通过前列腺组织中的旁分泌环路信号传导的AR调节已得到充分研究，但尽管该器官对呼吸道病毒感染有反应，但其通过肺中的IL 6自分泌环路的影响尚未得到充分研究。AR的化学抑制和RNA敲除利用肺细胞中的这些扰动确定了bZIP转录因子MAF是炎症的常见靶点。我们通过预测性计算机网络建模假设MAF是暴露于AR拮抗剂和病毒（SARS-Cov-2）感染的肺细胞中雄激素信号传导和炎症反应之间的共同介体。为了建立肺中AR抑制的背景，427个正常人肺样品的公共数据库揭示了AR表达，其水平不随性别或年龄显著变化（图S1 A）。这表明AR在正常肺中表达，而不是前列腺组织所特有的。用AR拮抗剂Enzalutamide表征其EC 50的6种肺细胞系亚组（表S1）在AR激动剂R1881存在下处理0.5、2、4、8或24 h（睾酮），这表明AR在A549细胞中的表达是负反馈调节的（图1A），而H226、H460、H2228和H3122细胞最低限度地响应长达24小时，除了H520（典型的鳞状肺细胞系）（图S1 B）。我们选择进一步表征AR在A549和H2228细胞中的早期（2小时）和晚期（24小时）表达。虽然Enzalutamide可主动取代激动剂R1881，反之亦然，并早在2 h至24 h诱导AR下调，但在A549细胞中，不存在R1881的Enzalutamide处理与对照处理相似，表明可逆的开关拮抗剂-激动剂相互作用长达24 h。然而，在H2228细胞中，类似的处理诱导了AR表达的轻微增加（图1 B）。与受R1881负调控的前列腺细胞不同，只有细支气管肺泡细胞（A549）（炎症和癌的细胞类型祖细胞）在去除激素处理的受控炭胎牛血清中显示出持续的AR信号传导。接下来，我们通过动态核质成像和定量确定AR在肺中是功能性的。虽然AR（红色）在具有配体R1881的A549和H2228细胞中均被有效转运至细胞核（图1C;图S2 A），但使用AR特异性siRNA（图S3和表S2）或恩杂鲁胺破坏并定量（图1D;图S2 B）的作用证明AR的siRNA敲低表型模仿恩杂鲁胺的作用。
Androgen receptor (AR) is a major transcription factor that plays a role in inflammatory response including interleukin-6 (IL6) signaling. 1 While AR regulation through paracrine loop signaling in prostate tissue is well-studied, its impact through an IL6 autocrine loop in the lung has not been well-studied despite the organ's response to respiratory viral infection. Chemical inhibition and RNA knockdown of AR identified a bZIP transcription factor MAF to be a common target of inflammation using these perturbations in lung cells. We hypothesized through a predictive in silico network modeling that MAF is a common mediator between androgen signaling and inflammatory response in lung cells exposed to AR antagonists and viral (SARS-Cov-2) infection.To establish a context for AR inhibition in the lung, a public database of 427 normal human lung samples revealed AR expression with levels not significantly varying by gender or age (Fig. S1A). This suggested that AR is expressed in normal lungs and is not unique to prostate tissue. A subset of six lung cell lines characterized with AR antagonist enzalutamide for their EC 50 (Table S1) was treated for 0.5, 2, 4, 8, or 24 h in the presence of AR agonist R1881 (testosterone), which revealed AR expression in A549 cells to be negatively feed-back regulated (Fig. 1 A) while H226, H460, H2228, and H3122 cells were minimally responsive up to 24 h, with the exception being H520, a typical squamous lung cell line (Fig. S1B). We chose to further characterize AR early (2 h) and late (24 h) expression in A549 and H2228 cells. While enzalutamide actively displaced the agonist R1881 and vice versa and induced AR down-regulation as early as 2 h up to 24 h, enzalutamide treatment in the absence of R1881 was similar to control treatment in A549 cells, suggesting a reversible on-off antagonist-agonist interaction up to 24 h. However, in H2228 cells, similar treatments induced a slight increase in AR expression (Fig. 1 B). Unlike prostate cells which are negatively regulated by R1881, only bronchioalveolar cells (A549), a cell-type progenitor for inflammation and carcinoma, showed sustained AR signaling in controlled charcoal fetal bovine serum stripped of hormone treatments. Next, we established that AR was functional in the lung through dynamic nuclear-cytoplasmic imaging and quantitation. While AR (red) was efficiently transported to the nucleus in both A549 and H2228 cells with ligand R1881 (Fig. 1 C; Fig. S2A), an effect that was disrupted using either AR-specific siRNAs (Fig. S3 and Table S2) or enzalutamide and quantified (Fig. 1 D; Fig. S2B), demonstrating that siRNA knockdown of AR phenocopies the effect of enzalutamide.
影响因子：
4.1
作者：
Culig, Zoran;Puhr, Martin
通讯作者：
Puhr, Martin
影响因子：
64.5
作者：
Blanco-Melo, Daniel;Nilsson-Payant, Benjamin E.;tenOever, Benjamin R.
通讯作者：
tenOever, Benjamin R.
影响因子：
4.8
作者：
Ueda, T;Bruchovsky, N;Sadar, MD
通讯作者：
Sadar, MD