Regulation of Toll/IL-1-receptor-mediated gene expression by the inducible nuclear protein IκBζ

Masahiro Yamamoto, Soh Yamazaki, Satoshi Uematsu, Shintaro Sato, Hiroaki Hemmmi, Katsuaki Hoshino, Tsuneyasu Kaisho, Hirotaka Kuwata, Osamu Takeuchi, Koichiro Takeshige, Tatsuya Saitoh, Shoji Yamaoka, Naoki Yamamoto, Shunsuke Yamamoto, Tatsushi Muta, Kiyoshi Takeda, Shizuo Akira

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345 Citations (Scopus)

Abstract

Toll-like receptors (TLRs) recognize microbial components and trigger the inflammatory and immune responses against pathogens. IκBβ (also known as MAIL and INAP) is an ankyrin-repeat-containing nuclear protein that is highly homologous to the IκB family member Bcl-3 (refs 1-6). Transcription of IκBζ is rapidly induced by stimulation with TLR ligands and interleukin-1 (IL-1). Here we show that IκBζ is indispensable for the expression of a subset of genes activated in TLR/IL-1R signalling pathways. IκBζ-deficient cells show severe impairment of IL-6 production in response to a variety of TLR ligands as well as IL-1, but not in response to tumour-necrosis factor-α. Endogenous IκBζ specifically associates with the p50 subunit of NF-κB, and is recruited to the NF-κB binding site of the IL-6 promoter on stimulation. Moreover, NF-κB1/p50-deficient mice show responses to TLR/IL-1R ligands similar to those of IκBζ-deficient mice. Endotoxin-induced expression of other genes such as Il12b and Csf2 is also abrogated in IκBζ-deficient macrophages. Given that the lipopolysaccharide-induced transcription of IκBζ occurs earlier than transcription of these genes, some TLR/IL-1R-mediated responses may be regulated in a gene expression process of at least two steps that requires inducible IκBζ.

Original languageEnglish
Pages (from-to)218-222
Number of pages5
JournalNature
Volume430
Issue number6996
DOIs
Publication statusPublished - 2004 Jul 8

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    Yamamoto, M., Yamazaki, S., Uematsu, S., Sato, S., Hemmmi, H., Hoshino, K., Kaisho, T., Kuwata, H., Takeuchi, O., Takeshige, K., Saitoh, T., Yamaoka, S., Yamamoto, N., Yamamoto, S., Muta, T., Takeda, K., & Akira, S. (2004). Regulation of Toll/IL-1-receptor-mediated gene expression by the inducible nuclear protein IκBζ. Nature, 430(6996), 218-222. https://doi.org/10.1038/nature02738