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

Abstract

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.

• Authors: Chenguang Fan, Qiang Li, Yulong Zhang, Xiaoming Liu, Meihui Luo, Duane Abbott, Weihong Zhou, John F Engelhardt
• Journal: The Journal of clinical investigation (J Clin Invest) Vol. 113 Issue 5 Pg. 746-55 (Mar 2004) ISSN: 0021-9738 [Print] United States
• PMID: 14991073 (Publication Type: Journal Article, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• 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)

Topics

• Animals
• Blotting, Western
• Cells, Cultured
• DNA, Complementary (metabolism)
• Endotoxins (metabolism)
• Hepatocytes (metabolism)
• Heterozygote
• I-kappa B Proteins (physiology)
• Inflammation
• Lipopolysaccharides (metabolism)
• Liver (injuries, metabolism, 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)