IκBα Deficiency Results in a Sustained NF-κB Response and Severe Widespread Dermatitis in Mice

The ubiquitous transcription factor NF-κB is an essential component in signal transduction pathways, in inflammation, and in the immune response. NF-κB is maintained in an inactive state in the cytoplasm by protein-protein interaction with IκBα. Upon stimulation, rapid degradation of IκBα allows nuclear translocation of NF-κB. To study the importance of IκBα in signal transduction, IκBα-deficient mice were derived by gene targeting. Cultured fibroblasts derived from IκBα-deficient embryos exhibit levels of NF-κB1, NF-κB2, RelA, c-Rel, and IκBβ similar to those of wild-type fibroblasts. A failure to increase nuclear levels of NF-κB indicates that cytoplasmic retention of NF-κB may be compensated for by other IκB proteins. Treatment of wild-type cells with tumor necrosis factor alpha (TNF-α) resulted in rapid, transient nuclear localization of NF-κB. IκBα-deficient fibroblasts are also TNF-α responsive, but nuclear localization of NF-κB is prolonged, thus demonstrating that a major irreplaceable function of IκBα is termination of the NF-κB response. Consistent with these observations, and with IκBα and NF-kB's role in regulating inflammatory and immune responses, is the normal development of IκBα-deficient mice. However, growth ceases 3 days after birth and death usually occurs at 7 to 10 days of age. An increased percentage of monocytes/macrophages was detected in spleen cells taken from 5-, 7-, and 9-day-old pups. Death is accompanied by severe widespread dermatitis and increased levels of TNF-α mRNA in the skin.