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Fra-1 protooncogene regulates il-6 expression in macrophages and promotes the generation of m2d macrophages

Academic Article
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Overview

authors

  • Wang, Q. S.
  • Ni, H.
  • Lan, L.
  • Wei, X. L.
  • Xiang, Rong
  • Wang, Y.

publication date

  • June 2010

journal

  • Cell Research  Journal

abstract

  • 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.

subject areas

  • Animals
  • Cell Differentiation
  • Cell Line, Tumor
  • Coculture Techniques
  • Female
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Immune Tolerance
  • Interleukin-6
  • Macrophages
  • Mammary Neoplasms, Experimental
  • Mice
  • Mice, Inbred BALB C
  • Promoter Regions, Genetic
  • Protein Binding
  • Proto-Oncogene Proteins c-fos
  • Up-Regulation
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Research

keywords

  • Fra-1
  • IL-6
  • M2d
  • co-culture
  • generation
  • phenotype
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Identity

International Standard Serial Number (ISSN)

  • 1001-0602

Digital Object Identifier (DOI)

  • 10.1038/cr.2010.52

PubMed ID

  • 20386569
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Additional Document Info

start page

  • 701

end page

  • 712

volume

  • 20

issue

  • 6

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