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- Title
Regulation of Toll/IL-1-receptor-mediated gene expression by the inducible nuclear protein I?B?
- Authors
Yamamoto, Masahiro; Yamazaki, Soh; Uematsu, Satoshi; Sato, Shintaro; Hemmi, Hiroaki; Hoshino, Katsuaki; Kaisho, Tsuneyasu; Kuwata, Hirotaka; Takeuchi, Osamu; Takeshige, Koichiro; Saitoh, Tatsuya; Yamaoka, Shoji; Yamamoto, Naoki; Yamamoto, Shunsuke; Muta, Tatsushi; Takeda, Kiyoshi; Akira, Shizuo
- Abstract
Toll-like receptors (TLRs) recognize microbial components and trigger the inflammatory and immune responses against pathogens. I?B? (also known as MAIL and INAP) is an ankyrin-repeat-containing nuclear protein that is highly homologous to the I?B family member Bcl-3 (refs 1-6). Transcription of I?B? is rapidly induced by stimulation with TLR ligands and interleukin-1 (IL-1). Here we show that I?B? is indispensable for the expression of a subset of genes activated in TLR/IL-1R signalling pathways. I?B?-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-a. Endogenous I?B? specifically associates with the p50 subunit of NF-?B, and is recruited to the NF-?B binding site of the IL-6 promoter on stimulation. Moreover, NF-?B1/p50-deficient mice show responses to TLR/IL-1R ligands similar to those of I?B?-deficient mice. Endotoxin-induced expression of other genes such as Il12b and Csf2 is also abrogated in I?B?-deficient macrophages. Given that the lipopolysaccharide-induced transcription of I?B? 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 I?B?.
- Subjects
IMMUNE response; PATHOGENIC microorganisms; PROTEINS; LIGANDS (Biochemistry); INTERLEUKIN-1; TUMOR necrosis factors; INTERLEUKIN-6
- Publication
Nature, 2004, Vol 430, Issue 6996, p218
- ISSN
0028-0836
- Publication type
Article
- DOI
10.1038/nature02738