IkappaBNS inhibits induction of a subset of Toll-like receptor-dependent genes and limits inflammation

Immunity. 2006 Jan;24(1):41-51. doi: 10.1016/j.immuni.2005.11.004.


Toll-like receptor (TLR)-mediated immune responses are downregulated by several mechanisms that affect signaling pathways. However, it remains elusive how TLR-mediated gene expression is differentially modulated. Here, we show that IkappaBNS, a TLR-inducible nuclear IkappaB protein, negatively regulates induction of a subset of TLR-dependent genes through inhibition of NF-kappaB activity. IkappaBNS-deficient macrophages and dendritic cells show increased TLR-mediated expression of genes such as IL-6 and IL-12p40, which are induced late after TLR stimulation. In contrast, IkappaBNS-deficient cells showed normal induction of genes that are induced early or induced via IRF-3 activation. LPS stimulation of IkappaBNS-deficient macrophages prolonged NF-kappaB activity at the specific promoters, indicating that IkappaBNS mediates termination of NF-kappaB activity at selective gene promoters. Moreover, IkappaBNS-deficient mice are highly susceptible to LPS-induced endotoxin shock and intestinal inflammation. Thus, IkappaBNS regulates inflammatory responses by inhibiting the induction of a subset of TLR-dependent genes through modulation of NF-kappaB activity.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Colitis / chemically induced
  • Colitis / genetics
  • Colitis / immunology*
  • Colon / pathology
  • Dendritic Cells / immunology
  • Interleukin-12 / antagonists & inhibitors*
  • Interleukin-12 / genetics
  • Interleukin-12 Subunit p40
  • Interleukin-6 / antagonists & inhibitors*
  • Interleukin-6 / genetics
  • Intracellular Signaling Peptides and Proteins
  • Lipopolysaccharides / toxicity
  • Macrophages / immunology
  • Mice
  • Mice, Mutant Strains
  • NF-kappa B / metabolism
  • Promoter Regions, Genetic
  • Protein Subunits / antagonists & inhibitors*
  • Protein Subunits / genetics
  • Proteins / genetics
  • Proteins / metabolism*
  • Shock, Septic / chemically induced
  • Shock, Septic / genetics
  • Shock, Septic / immunology
  • Toll-Like Receptors / metabolism*
  • Transcription Factor RelA / metabolism
  • Up-Regulation


  • IkappaBNS protein, mouse
  • Interleukin-12 Subunit p40
  • Interleukin-6
  • Intracellular Signaling Peptides and Proteins
  • Lipopolysaccharides
  • NF-kappa B
  • Protein Subunits
  • Proteins
  • Toll-Like Receptors
  • Transcription Factor RelA
  • Interleukin-12