IkappaBalpha and IkappaBbeta possess injury context-specific functions that uniquely influence hepatic NF-kappaB induction and inflammation.
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.
Molecular Biology Program, College of Medicine, University of Iowa, Iowa City, Iowa 52242, USA.
Chenguang
C
Fan
Qiang
Q
Li
Yulong
Y
Zhang
Xiaoming
X
Liu
Meihui
M
Luo
Duane
D
Abbott
Weihong
W
Zhou
John F
JF
Engelhardt
D000818:Animals; D015153:Blotting, Western; D002478:Cells, Cultured; D018076:DNA, Complementary / Q000378:metabolism; D004731:Endotoxins / Q000378:metabolism; D022781:Hepatocytes / Q000378:metabolism; D006579:Heterozygote; D020672:I-kappa B Proteins / Q000502:physiology*; D007249:Inflammation; D008070:Lipopolysaccharides / Q000378:metabolism; D008099:Liver / Q000293:injuries / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D008822:Mice, Transgenic; D008957:Models, Genetic; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000378:metabolism*; D010766:Phosphorylation; D016392:Proto-Oncogene Proteins pp60(c-src) / Q000378:metabolism; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D014443:Tyrosine / Q000378:metabolism
D018076:DNA, Complementary; D004731:Endotoxins; C083487:I kappa B beta protein; D020672:I-kappa B Proteins; D008070:Lipopolysaccharides; D016328:NF-kappa B; C000606205:Nfkbia protein, mouse; D014409:Tumor Necrosis Factor-alpha; D000072000:NF-KappaB Inhibitor alpha; D014443:Tyrosine; D016392:Proto-Oncogene Proteins pp60(c-src)