Authors' Affiliations: Laboratory of Molecular Genetics, Biostatistics Branch, Laboratory of Respiratory Biology, National Institute of Environmental Health Sciences (NIEHS), NIH, Research Triangle Park; and Epidemiology, Gillings School of Global Public Health, University of North Carolina, Chapel Hill, North Carolina.
Cancer Res. 2014 Apr 15;74(8):2182-92. doi: 10.1158/0008-5472.CAN-13-1070.
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 (TAM) 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, coregulate induction of proinflammatory genes in primary human monocytes and macrophages. Using Nutlin-3 as a tool, we demonstrate that p53 and NF-κB rapidly and highly induce interleukin (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. In addition, 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 (TCM)]. Compared with 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 proinflammatory 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.
巨噬细胞是哨兵免疫细胞，可检测组织微环境，在对外源性刺激和肿瘤发生等内源性事件作出反应时释放细胞因子。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（TAM）及其产物也可能促进肿瘤进展。NF-κB 在巨噬细胞引发的炎症反应中很突出，而 p53 在巨噬细胞对环境挑战（包括化疗或 TAMs）的反应中的作用却知之甚少。在这里，我们报告 NF-κB 和 p53 通常在癌细胞中具有相反的作用，它们共同调节原代人单核细胞和巨噬细胞中促炎基因的诱导。我们使用 Nutlin-3 作为工具，证明 p53 和 NF-κB 通过结合其启动子快速且高度诱导白细胞介素（IL）-6 的产生。转录组分析显示 p53/NF-κB 对免疫反应基因的全局调控，包括几种趋化因子，这些基因有效地诱导了人中性粒细胞的迁移。此外，我们还表明，肿瘤细胞旁分泌因子激活的 p53 在 TAM 模型系统（肿瘤条件性巨噬细胞（TCM））中诱导巨噬细胞中 IL-6 的基础水平升高。与正常巨噬细胞相比，TCM 显示出更高的 p53 水平，增强的 p53 与 IL-6 启动子的结合，以及 p53 抑制后 IL-6 水平降低。总之，我们描述了一种人类巨噬细胞通过 p53 和 NF-κB 整合信号来驱动促炎细胞因子诱导的机制。我们的结果表明巨噬细胞 p53 在调节肿瘤微环境方面具有新的作用，并提出了一种新的机制，即作用于 p53 充足的巨噬细胞和前体细胞单核细胞的 p53 激活化疗药物可能间接影响缺乏功能性 p53 的肿瘤。
