Volume 20, No 6, Jun 2010
ISSN: 1001-0602
EISSN: 1748-7838 2018
impact factor 17.848*
(Clarivate Analytics, 2019)
Volume 20 Issue 6, June 2010: 701-712
ORIGINAL ARTICLES
Fra-1 protooncogene regulates IL-6 expression in macrophages and promotes the generation of M2d macrophages
Qingshan Wang1, Hong Ni1, Lan Lan2, Xiaoli Wei1, Rong Xiang1 and Yue Wang1
1School of Medicine, Nankai University, Tianjin 300071, China
2Tianjin Medical University, Tianjin Cancer Hospital, Tianjin 300060, China
Correspondence: Yue Wang,(wangyue@nankai.edu.cn)
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.
Cell Research (2010) 20:701-712. doi:10.1038/cr.2010.52; published online 13 April 2010
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