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International Immunology Advance Access originally published online on February 27, 2009
International Immunology 2009 21(4):457-465; doi:10.1093/intimm/dxp015
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© The Japanese Society for Immunology. 2009. All rights reserved. For permissions, please e-mail: journals.permissions@oxfordjournals.org

Fra-1 negatively regulates lipopolysaccharide-mediated inflammatory responses

Hideaki Morishita1, Fumiji Saito1,2, Hisako Kayama1,2,3, Koji Atarashi1,2,3, Hirotaka Kuwata1, Masahiro Yamamoto2,3 and Kiyoshi Takeda1,2,3

1 Department of Molecular Genetics, Medical Institute of Bioregulation, Kyushu University, Fukuoka 812-8582, Japan
2 Laboratory of Immune Regulation, Department of Microbiology and Immunology, Graduate School of Medicine
3 WPI Immunology Frontier Research Center, Osaka University, Suita, Osaka 565-0871, Japan

Correspondence to: K. Takeda; E-mail: ktakeda{at}ongene.med.osaka-u.ac.jp

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.

Keywords: AP-1, gene expression, inflammation, innate immunity, Toll-like receptor

Transmitting editor: T. Watanabe

Received 4 December 2008, accepted 27 January 2009.


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