期刊
CELL RESEARCH
卷 20, 期 6, 页码 701-712出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/cr.2010.52
关键词
Fra-1; M2d; IL-6; generation; phenotype; co-culture
类别
资金
- National Basic Research Program of China (973 Program) [2007CB914804]
- National High Technology Research and Development Program of China (863 Program) [2007AA021010]
- Foundation of the Ministry of Education of China for Returned Scholars
- Key Project of the Science & Technology Pillar Program of Tianjin [09JCYBJC10800]
- Innovative Research Foundation of Nankai University
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.
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