p53 and NF-κB coregulate proinflammatory gene responses in human macrophages.
p53 and NF-κB coregulate proinflammatory gene responses in human macrophages.
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DOI：
10.1158/0008-5472.can-13-1070
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发表时间：
2014-04-15
期刊：
影响因子：
11.2
通讯作者：
Resnick MA
中科院分区：
文献类型：
--
作者：
Lowe JM;Menendez D;Bushel PR;Shatz M;Kirk EL;Troester MA;Garantziotis S;Fessler MB;Resnick MA
巨噬细胞是研究组织微环境的前哨免疫细胞，在应对外源性损伤和内源性事件(如肿瘤发生)时释放细胞因子。巨噬细胞介导肿瘤监视和治疗诱导的肿瘤消退；然而，肿瘤相关巨噬细胞(TAMs)及其产物也可能促进肿瘤进展。虽然核因子-κB在巨噬细胞启动的炎症反应中很突出，但对于P53在巨噬细胞对环境挑战(包括化疗或TAMs)的反应中所起的作用知之甚少。在这里，我们报告了在癌细胞中通常具有相反作用的NF-κB和P53，它们共同调节原代人类单核细胞和巨噬细胞中促炎基因的诱导。以Nutlin-3为工具，我们证明了P53和NF-κB通过与其启动子结合而快速而高效地诱导IL-6。转录组分析显示，P53/NF-κB共同调节免疫反应基因，包括几种趋化因子，有效地诱导了人中性粒细胞的迁移。此外，我们发现，在模型系统(肿瘤条件巨噬细胞[TCM])中，由肿瘤细胞旁分泌因子激活的P53可以诱导高基础水平的巨噬细胞IL-6。与正常巨噬细胞相比，TCM显示更高的P53水平，增强P53与IL-6启动子的结合，并降低P53抑制后的IL-6水平。综上所述，我们描述了一种机制，人类巨噬细胞通过P53和NF-κB整合信号来驱动促炎细胞因子的诱导。我们的结果暗示了巨噬细胞P53在调节肿瘤微环境中的新作用，并提示了一种潜在的机制，即激活P53的化疗药物作用于P53充足的巨噬细胞和前体单核细胞，可能间接影响缺乏功能性P53的肿瘤。
Macrophages are sentinel immune cells that survey the tissue microenvironment, releasing cytokines in response to both exogenous insults and endogenous events such as tumorigenesis. Macrophages mediate tumor surveillance and therapy-induced tumor regression; however, Tumor Associated Macrophages (TAMs) and their products may also promote tumor progression. Whereas NF-κB is prominent in macrophage-initiated inflammatory responses, little is known about the role of p53 in macrophage responses to environmental challenge including chemotherapy or in TAMs. Here, we report that NF-κB and p53, which generally have opposing effects in cancer cells, co-regulate induction of pro-inflammatory genes in primary human monocytes and macrophages. Using Nutlin-3 as a tool, we demonstrate that p53 and NF-κB rapidly and highly induce IL-6 by binding to its promoter. Transcriptome analysis revealed global p53/NF-κB co-regulation of immune response genes including several chemokines, which effectively induced human neutrophil migration. Additionally, we show that p53, activated by tumor cell paracrine factors, induces high basal levels of macrophage IL-6 in a TAM model system (Tumor-conditioned Macrophages [TCMs]). Compared to normal macrophages, TCMs exhibited higher p53 levels, enhanced p53 binding to the IL-6 promoter and reduced IL-6 levels upon p53 inhibition. Taken together, we describe a mechanism by which human macrophages integrate signals through p53 and NF-κB to drive pro-inflammatory cytokine induction. Our results implicate a novel role for macrophage p53 in conditioning the tumor microenvironment and suggest a potential mechanism by which p53-activating chemotherapeutics, acting upon p53-sufficient macrophages and precursor monocytes, may indirectly impact tumors lacking functional p53.