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

Toll-like receptors (TLRs) recognize microbial components and trigger the inflammatory and immune responses against pathogens. IkappaBzeta (also known as MAIL and INAP) is an ankyrin-repeat-containing nuclear protein that is highly homologous to the IkappaB family member Bcl-3 (refs 1-6). Transcription of IkappaBzeta is rapidly induced by stimulation with TLR ligands and interleukin-1 (IL-1). Here we show that IkappaBzeta is indispensable for the expression of a subset of genes activated in TLR/IL-1R signalling pathways. IkappaBzeta-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-alpha. Endogenous IkappaBzeta specifically associates with the p50 subunit of NF-kappaB, and is recruited to the NF-kappaB binding site of the IL-6 promoter on stimulation. Moreover, NF-kappaB1/p50-deficient mice show responses to TLR/IL-1R ligands similar to those of IkappaBzeta-deficient mice. Endotoxin-induced expression of other genes such as Il12b and Csf2 is also abrogated in IkappaBzeta-deficient macrophages. Given that the lipopolysaccharide-induced transcription of IkappaBzeta 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 IkappaBzeta.

Pubmed ID: 15241416

Authors

  • Yamamoto M
  • Yamazaki S
  • Uematsu S
  • Sato S
  • Hemmi 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

Journal

Nature

Publication Data

July 8, 2004

Associated Grants

None

Mesh Terms

  • Adaptor Proteins, Signal Transducing
  • Animals
  • Gene Expression Regulation
  • Interleukin-12
  • Interleukin-6
  • Kinetics
  • Ligands
  • Lipopolysaccharides
  • Membrane Glycoproteins
  • Mice
  • Mice, Knockout
  • NF-kappa B
  • NF-kappa B p50 Subunit
  • Nuclear Proteins
  • Promoter Regions, Genetic
  • Receptors, Cell Surface
  • Receptors, Interleukin-1
  • Response Elements
  • Signal Transduction
  • Toll-Like Receptors
  • Tumor Necrosis Factor-alpha
  • Up-Regulation