Defective feedback regulation of NF-κB underlies Sjogren's syndrome in mice with mutated κB enhancers of the IκBα promoter

Feedback regulation of transcription factor NF-kappa B by its inhibitor I kappa B alpha plays an essential role in control of NF-kappa B activity. To understand the biological significance of I kappa B alpha-mediated feedback regulation of NF-kappa B, we generated mice harboring mutated kappa B enhancers in the promoter of the I kappa B alpha gene (I kappa B alpha(M/M)) to inhibit NF-kappa B-regulated I kappa B alpha expression. Here, we report that these mutant mice are defective in NF-kappa B-induced expression of I kappa B alpha. This defective feedback regulation of NF-kappa B by I kappa B alpha not only altered activity of NF-kappa B, but also the expression of NF-kappa B-regulated genes. As a result, I kappa B alpha(M/M), the homozygous knock-in mice with mutated kappa B enhancers in the I kappa B alpha 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 alpha 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.