期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2010
卷号：107
期号：34
页码：15193-15198
DOI：10.1073/pnas.1005533107
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：Feedback regulation of transcription factor NF-{kappa}B by its inhibitor I{kappa}B plays an essential role in control of NF-{kappa}B activity. To understand the biological significance of I{kappa}B-mediated feedback regulation of NF-{kappa}B, we generated mice harboring mutated {kappa}B enhancers in the promoter of the I{kappa}B gene (I{kappa}BM/M) to inhibit NF-{kappa}B-regulated I{kappa}B expression. Here, we report that these mutant mice are defective in NF-{kappa}B-induced expression of I{kappa}B. This defective feedback regulation of NF-{kappa}B by I{kappa}B not only altered activity of NF-{kappa}B, but also the expression of NF-{kappa}B-regulated genes. As a result, I{kappa}BM/M, the homozygous knock-in mice with mutated {kappa}B enhancers in the I{kappa}B promoter, acquire shorten life span, hypersensitivity to septic shock, abnormal T-cell development and activation, and Sjogren's Syndrome. These findings therefore demonstrate that the I{kappa}B-mediated feedback regulation of NF-{kappa}B has an essential role in controlling T-cell development and functions, provide mechanistic insight into the development of Sjogren's Syndrome, and suggest the potential of NF-{kappa}B signaling as a therapeutic target for Sjogren's Syndrome and other autoimmune diseases.
关键词：autoimmunity ; inflammation ; T-cell development
