Fra-1 negatively regulates lipopolysaccharide-mediated inflammatory responses

Hideaki Morishita, Fumiji Saito, Hisako Kayama, Koji Atarashi, Hirotaka Kuwata, Masahiro Yamamoto, Kiyoshi Takeda

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9 Citations (Scopus)

Abstract

Stimulation of macrophages with a Toll-like receptor ligand, LPS, facilitates gene expression. The activator protein-1 (AP-1) family of transcription factors mediates these responses. However, c-Fos, a member of the AP-1 family, has been shown to inhibit LPS-induced gene expression in macrophages. In this study, we analyzed the role of Fos-related antigen-1 (Fra-1), another member of the AP-1 family of transcription factors, in LPS-induced responses in RAW264.7 macrophages. Fra-1 was induced in LPS-stimulated macrophages with delayed time kinetics compared with c-Fos. Lentiviral introduction of Fra-1 blocked LPS-induced expression of pro-inflammatory mediators at the protein and mRNA levels. A Fra-1 mutant, which lacks the basic leucine zipper domain required for heterodimer formation and DNA binding, did not inhibit LPS-induced responses. c-Fos bound to the AP-1-binding site early, but afterward it was replaced by Fra-1 in LPS-stimulated macrophages. Over-expression of Fra-1 induced its association with Jun proteins and stable DNA binding from an early time point following LPS stimulation. These findings indicate that Fra-1 suppresses LPS-induced mRNA expression by binding to the AP-1-binding site. RNAi-mediated knockdown of Fra-1 in RAW264.7 macrophages resulted in enhanced LPS-induced expression of a subset of genes. Thus, like c-Fos, Fra-1 negatively regulates LPS-induced responses in RAW264.7 macrophages.

Original languageEnglish
Pages (from-to)457-465
Number of pages9
JournalInternational immunology
Volume21
Issue number4
DOIs
Publication statusPublished - 2009 Apr 8
Externally publishedYes

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Keywords

  • AP-1
  • Gene expression
  • Inflammation
  • Innate immunity
  • Toll-like receptor

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

Cite this

Morishita, H., Saito, F., Kayama, H., Atarashi, K., Kuwata, H., Yamamoto, M., & Takeda, K. (2009). Fra-1 negatively regulates lipopolysaccharide-mediated inflammatory responses. International immunology, 21(4), 457-465. https://doi.org/10.1093/intimm/dxp015