Defective feedback regulation of NF-kB underlies Sj？gren's syndrome in mice with mutated kB enhancers of the lkBa promoter

论文题目:

Defective feedback regulation of NF-κB underlies Sj？gren’s syndrome in mice with mutated κB enhancers of the IκBα promoter

作者:

Bailu Peng, Jianhua Ling, Andrew Joon Lee, Zilai Wang, Zhe Chang, Wei Jin, Ya’an Kang, Richard Zhang,David Shim, Huamin Wang, Jason B. Fleming, Hui Zheng, Shao-Cong Sun, and Paul J. Chiao

年:

2010

卷:

107

期:

34

页:

15193-15198

联系作者:

彭白露

发表期刊:

Proceedings of the National Academy of Sciences of the United States of America

ISSN:

0027-8424

原文链接:

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摘要:

Feedback regulation of transcription factor NF-κB by its inhibitor IκBα plays an essential role in control of NF-κB activity. To understand the biological significance of IκBα-mediated feedback regulationof NF-κB,we generated mice harboring mutated κB enhancers in the promoter of the IκBα gene (IκBα^M/M) to inhibit NF-κB–regulated IκBα expression. Here, we report that these mutant mice are defective in NF-κB–induced expression of IκBα. This defective feedback regulation of NF-κB by IκBα not only altered activity of NF-κB, but also the expression of NF-κB–regulated genes. As a result, IκBα^M/M, the homozygous knock-in mice with mutated κB enhancers in the IκBα promoter, acquire shorten life span, hypersensitivity to septic shock, abnormal T-cell development and activation, and Sj？gren’sSyndrome. These findings therefore demonstrate that the IκBα- mediated feedback regulation of NF-κB has an essential role in controlling T-cell development and functions, provide mechanistic insight into the development of Sj？gren’s Syndrome, and suggest the potential of NF-κB signaling as a therapeutic target for Sj？gren’s Syndrome and other autoimmune diseases.