Fra-1 negatively regulates lipopolysaccharide-mediated inflammatory responses.
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.
Morishita
Hideaki
H
Department of Molecular Genetics, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan.
Saito
Fumiji
F
Kayama
Hisako
H
Atarashi
Koji
K
Kuwata
Hirotaka
H
Yamamoto
Masahiro
M
Takeda
Kiyoshi
K
D000818:Animals; D055785:Gene Knockdown Techniques; D008070:Lipopolysaccharides / Q000494:pharmacology; D008264:Macrophages / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D016760:Proto-Oncogene Proteins c-fos / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D016755:Proto-Oncogene Proteins c-jun / Q000276:immunology / Q000378:metabolism*; D034622:RNA Interference / Q000276:immunology / Q000502:physiology; D018808:Transcription Factor AP-1 / Q000276:immunology / Q000378:metabolism*; D000099169:Fos-Related Antigen 1
D008070:Lipopolysaccharides; D016760:Proto-Oncogene Proteins c-fos; D016755:Proto-Oncogene Proteins c-jun; D018808:Transcription Factor AP-1; D000099169:Fos-Related Antigen 1