Defective feedback regulation of NF-κB underlies Sjögren ’ s syndrome in mice with mutated κB enhancers of the IκBα promoter
- 9 August 2010
- journal article
- research article
- Published by Proceedings of the National Academy of Sciences in Proceedings of the National Academy of Sciences of the United States of America
- Vol. 107 (34), 15193-15198
- https://doi.org/10.1073/pnas.1005533107
Abstract
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 regulation of NF-κB, we generated mice harboring mutated κB enhancers in the promoter of the IκBα gene (IκBαM/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, IκBαM/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 Sjögren’s Syndrome. 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 Sjögren’s Syndrome, and suggest the potential of NF-κB signaling as a therapeutic target for Sjögren’s Syndrome and other autoimmune diseases.Keywords
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