Fra-1 protooncogene regulates IL-6 expression in macrophages and promotes the generation of M2d macrophages
Fra-1 protooncogene regulates IL-6 expression in macrophages and promotes the generation of M2d macrophages
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Fra-1原癌基因调节巨噬细胞中IL-6的表达并促进M2d巨噬细胞的生成
DOI：
10.1038/cr.2010.52
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发表时间：
2010-06-01
期刊：
影响因子：
44.1
通讯作者：
Wang, Yue
中科院分区：
文献类型：
--
作者：
Wang, Qingshan;Ni, Hong;Wang, Yue
肿瘤微环境（TME）在肿瘤细胞的生长中发挥着重要作用。作为 TME 的主要炎症成分，M2d 巨噬细胞受到 TME 的教育，从而发挥免疫抑制作用，促进肿瘤转移和进展。 Fra-1 与 Jun 伴侣形成激活蛋白 1 异二聚体并驱动基因转录。 Fra-1被认为会极大地诱导肿瘤的发生和进展。然而，迄今为止，人们对 Fra-1 在 M2d 巨噬细胞生成中的功能作用知之甚少。在这里，我们证明了 4T1 乳腺癌细胞与 RAW264 共培养。 7 巨噬细胞，倾斜 RAW264。 7巨噬细胞分化为M2d巨噬细胞。 4T1 细胞刺激 RAW264 中 Fra-1 的从头过度表达。 7 细胞，然后 Fra-1 与白细胞介素 6 (IL-6) 启动子结合，增加 RAW264 中细胞因子 IL-6 的产生。 7 个细胞。 IL-6 以自分泌方式影响 RAW264。 7巨噬细胞分化为M2d巨噬细胞。这些发现为如何逆转 M2d 巨噬细胞诱导的免疫耐受以提高免疫治疗方法的疗效提供了新的见解。
The tumor microenvironment (TME) plays a prominent role in the growth of tumor cells. As the major inflammatory component of the TME, M2d macrophages are educated by the TME such that they adopt an immunosuppressive role that promotes tumor metastasis and progression. Fra-1 forms activator protein-1 heterodimers with Jun partners and drives gene transcription. Fra-1 is thought to drastically induce tumorigenesis and progression. However, the functional role of Fra-1 in the generation of M2d macrophages is poorly understood to date. Here, we demonstrate that 4T1 mammary carcinoma cells, when co-cultured with RAW264. 7 macrophage cells, skew the RAW264. 7 macrophage cell differentiation into M2d macrophages. The 4T1 cells stimulate de novo overexpression of Fra-1 in RAW264. 7 cells, and then Fra-1 binds to the interleukin 6 (IL-6) promoter to increase the production of the cytokine IL-6 in RAW264. 7 cells. IL-6 acts in an autocrine fashion to skew RAW264. 7 macrophage cell differentiation into M2d macrophages. These findings open new insights into how to reverse M2d macrophage-induced immune tolerance to improve the efficacy of immunotherapeutic approaches.