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IκBα and IκBβ possess injury context-specific functions that uniquely influence hepatic NF-κB induction and inflammation
Chenguang Fan, … , Weihong Zhou, John F. Engelhardt
Chenguang Fan, … , Weihong Zhou, John F. Engelhardt
Published March 1, 2004
Citation Information: J Clin Invest. 2004;113(5):746-755. https://doi.org/10.1172/JCI17337.
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Article Immunology

IκBα and IκBβ possess injury context-specific functions that uniquely influence hepatic NF-κB induction and inflammation

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Abstract

IκB proteins play an important role in regulating NF-κB induction following a diverse range of environmental injuries. Studies evaluating IκBβ knock-in mice (AKBI), in which the IκBα gene is replaced by the IκBβ cDNA, have uncovered divergent properties of IκBα and IκBβ that influence their ability to activate hepatic NF-κB and subsequent downstream proinflammatory processes in a stimulus-specific manner. While AKBI mice demonstrated identical levels of hepatic NF-κB activation in response to endotoxin, a significantly reduced level of hepatic NF-κB activation was observed in AKBI mice after liver ischemia/reperfusion (I/R) injury. This reduced level of NF-κB activation in AKBI mice after liver I/R also correlated with decreased induction of serum TNF-α, 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 IκBα, but not IκBβ, to properly regulate NF-κB induction during the acute phase of I/R injury is due to injury context–specific activation of c-Src and subsequent tyrosine phosphorylation of IκBα on Tyr42. These results demonstrate that IκBα and IκBβ play unique injury context–specific roles in activating NF-κB–mediated proinflammatory responses and suggest that strategies aimed at inhibiting IκBα 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

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Figure 8

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LPS and I/R liver injury induce IKK activation with differing kinetics. ...
LPS and I/R liver injury induce IKK activation with differing kinetics. AKBI or heterozygous (Het) littermates were challenged with LPS (1 μg/g body weight, i.v.) or I/R, and whole-cell extracts were prepared at 60 and/or 180 minutes after reperfusion or after LPS treatment. The IKK complex was immunoprecipitated with an anti-IKKα/β Ab and used in an in vitro kinase assay. The ability of immunoprecipitated IKK to directly phosphorylate GST-IκBα following (A) LPS treatment or (B) I/R in AKBI mice or heterozygous mice was then compared in the presence of [γ-32P]ATP. Kinase reactions were evaluated by SDS-PAGE, followed by transfer to a nylon membrane. Top membranes in each panel were exposed to film, and then bottom membranes in each panel were immunoblotted with an anti-GST Ab to confirm equal loading (bottom panel).

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