Fra-1 negatively regulates lipopolysaccharide-mediated inflammatory responses

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

Research output: Contribution to journalArticle

8 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
Externally publishedYes

Fingerprint

Lipopolysaccharides
Transcription Factor AP-1
Macrophages
Protein Binding
Transcription Factors
Binding Sites
Gene Expression
fos-related antigen 1
Leucine Zippers
Messenger RNA
Toll-Like Receptors
DNA-Binding Proteins
RNA Interference
Ligands
DNA
Genes
Proteins

Keywords

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

ASJC Scopus subject areas

  • 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

Fra-1 negatively regulates lipopolysaccharide-mediated inflammatory responses. / Morishita, Hideaki; Saito, Fumiji; Kayama, Hisako; Atarashi, Koji; Kuwata, Hirotaka; Yamamoto, Masahiro; Takeda, Kiyoshi.

In: International Immunology, Vol. 21, No. 4, 2009, p. 457-465.

Research output: Contribution to journalArticle

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, vol. 21, no. 4, pp. 457-465. https://doi.org/10.1093/intimm/dxp015
Morishita, Hideaki ; Saito, Fumiji ; Kayama, Hisako ; Atarashi, Koji ; Kuwata, Hirotaka ; Yamamoto, Masahiro ; Takeda, Kiyoshi. / Fra-1 negatively regulates lipopolysaccharide-mediated inflammatory responses. In: International Immunology. 2009 ; Vol. 21, No. 4. pp. 457-465.
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