IL-6 augments IL-4-induced polarization of primary human macrophages through synergy of STAT3, STAT6 and BATF transcription factors
IL-6 augments IL-4-induced polarization of primary human macrophages through synergy of STAT3, STAT6 and BATF transcription factors
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DOI：
10.1080/2162402x.2018.1494110
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发表时间：
2018-01-01
期刊：
影响因子：
7.2
通讯作者：
Namgaladze, Dmitry
中科院分区：
文献类型：
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作者：
Gupta, Sahil;Jain, Arpit;Namgaladze, Dmitry
肿瘤微环境中的巨噬细胞对复杂的细胞因子信号做出反应。这些反应如何影响肿瘤相关巨噬细胞(TAMs)的表型尚不完全清楚。在这里，我们探索了肿瘤环境中的细胞因子，白介素6和白介素4如何相互作用，影响原代人类单核细胞来源的巨噬细胞(HMDM)的靶基因表达。我们发现，IL-4和IL-6的双重刺激协同改变了基因的表达。在协同诱导的基因中，有几个具有已知促肿瘤特性的靶点，如CC-趋化因子配体18(CCL18)、转化生长因子α(TGFA)或CD274(程序性细胞死亡1配体1(PD-L1))。我们发现信号转导和转录激活因子(STAT)家族的转录因子STAT3和STAT6与协同诱导基因的调节区紧密结合。STAT3和STAT6共同结合进一步诱导碱性亮氨酸拉链ATF样转录因子(BATF)，参与协同诱导靶基因表达。功能分析显示，与与单一细胞因子处理的hMDM的培养液孵育的细胞相比，来自共处理的hMDM的条件培养液增加了MCF-7和MDA-MB 231肿瘤细胞的运动能力。不同细胞因子极化的hMDM与T细胞共培养后的流式细胞仪分析表明，双重刺激以PD-L1依赖的方式促进hMDM的免疫抑制特性。临床资料分析显示，乳腺癌患者肿瘤间质中BATF和标志物的表达均高于正常乳腺组织间质。总而言之，我们的发现表明，IL-4和IL-6协同作用改变了人类巨噬细胞转录组，赋予hMDM促肿瘤特性。
Macrophages in the tumor microenvironment respond to complex cytokine signals. How these responses shape the phenotype of tumor-associated macrophages (TAMs) is incompletely understood. Here we explored how cytokines of the tumor milieu, interleukin (IL)-6 and IL-4, interact to influence target gene expression in primary human monocyte-derived macrophages (hMDMs). We show that dual stimulation with IL-4 and IL-6 synergistically modified gene expression. Among the synergistically induced genes are several targets with known pro-tumorigenic properties, such as CC-chemokine ligand 18 (CCL18), transforming growth factor alpha (TGFA) or CD274 (programmed cell death 1 ligand 1 (PD-L1)). We found that transcription factors of the signal transducer and activator of transcription (STAT) family, STAT3 and STAT6 bind regulatory regions of synergistically induced genes in close vicinity. STAT3 and STAT6 co-binding further induces the basic leucine zipper ATF-like transcription factor (BATF), which participates in synergistic induction of target gene expression. Functional analyses revealed increased MCF-7 and MDA-MB 231 tumor cell motility in response to conditioned media from co-treated hMDMs compared to cells incubated with media from single cytokine-treated hMDMs. Flow cytometric analysis of T cell populations upon co-culture with hMDMs polarized by different cytokines indicated that dual stimulation promoted immunosuppressive properties of hMDMs in a PD-L1-dependent manner. Analysis of clinical data revealed increased expression of BATF together with TAM markers in tumor stroma of breast cancer patients as compared to normal breast tissue stroma. Collectively, our findings suggest that IL-4 and IL-6 cooperate to alter the human macrophage transcriptome, endowing hMDMs with pro-tumorigenic properties.