IkappaBalpha and IkappaBbeta possess injury context-specific functions that uniquely influence hepatic NF-kappaB induction and inflammation

J Clin Invest. 2004 Mar;113(5):746-55. doi: 10.1172/JCI17337.


IkappaB proteins play an important role in regulating NF-kappaB induction following a diverse range of environmental injuries. Studies evaluating IkappaBbeta knock-in mice (AKBI), in which the IkappaBalpha gene is replaced by the IkappaBbeta cDNA, have uncovered divergent properties of IkappaBalpha and IkappaBbeta that influence their ability to activate hepatic NF-kappaB and subsequent downstream proinflammatory processes in a stimulus-specific manner. While AKBI mice demonstrated identical levels of hepatic NF-kappaB activation in response to endotoxin, a significantly reduced level of hepatic NF-kappaB activation was observed in AKBI mice after liver ischemia/reperfusion (I/R) injury. This reduced level of NF-kappaB activation in AKBI mice after liver I/R also correlated with decreased induction of serum TNF-alpha, reduced hepatic inflammation, and increased survival. In contrast, no differences in any of these indicators were observed between AKBI mice and WT littermates after a lethal injection of LPS. Molecular studies suggest that the specificity of IkappaBalpha, but not IkappaBbeta, to properly regulate NF-kappaB induction during the acute phase of I/R injury is due to injury context-specific activation of c-Src and subsequent tyrosine phosphorylation of IkappaBalpha on Tyr42. These results demonstrate that IkappaBalpha and IkappaBbeta play unique injury context-specific roles in activating NF-kappaB-mediated proinflammatory responses and suggest that strategies aimed at inhibiting IkappaBalpha gene expression may be of potential therapeutic benefit in hepatic I/R injury.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Blotting, Western
  • Cells, Cultured
  • DNA, Complementary / metabolism
  • Endotoxins / metabolism
  • Hepatocytes / metabolism
  • Heterozygote
  • I-kappa B Proteins / physiology*
  • Inflammation*
  • Lipopolysaccharides / metabolism
  • Liver / injuries
  • Liver / metabolism
  • Liver / pathology*
  • Mice
  • Mice, Transgenic
  • Models, Genetic
  • NF-KappaB Inhibitor alpha
  • NF-kappa B / metabolism*
  • Phosphorylation
  • Proto-Oncogene Proteins pp60(c-src) / metabolism
  • Time Factors
  • Tumor Necrosis Factor-alpha / metabolism
  • Tyrosine / metabolism


  • DNA, Complementary
  • Endotoxins
  • I kappa B beta protein
  • I-kappa B Proteins
  • Lipopolysaccharides
  • NF-kappa B
  • Nfkbia protein, mouse
  • Tumor Necrosis Factor-alpha
  • NF-KappaB Inhibitor alpha
  • Tyrosine
  • Proto-Oncogene Proteins pp60(c-src)