I-KAPPA-B-ALPHA DEFICIENCY RESULTS IN A SUSTAINED NF-KAPPA-B RESPONSEAND SEVERE WIDESPREAD DERMATITIS IN MICE

The ubiquitous transcription factor NF-kappa B is an essential compone nt in signal transduction pathways, in inflammation, and in the immune response, NF-kappa B is maintained in an inactive state in the cytopl asm by protein-protein interaction with I kappa B alpha. Upon stimulat ion, rapid degradation of I kappa B alpha allows nuclear translocation of NF-kappa B. To study the importance of I kappa B alpha in signal t ransduction, I kappa B alpha-deficient mice mere derived by gene targe ting, Cultured fibroblasts derived from I kappa B alpha-deficient embr yos exhibit levels of NF-kappa B1, NF-kappa B2, RelA, c-Rel, and I kap pa B beta similar to those of wild-type fibroblasts, A failure to incr ease nuclear levels of NF-kappa B indicates that cytoplasmic retention of NF-kappa B may be compensated for by other I kappa B proteins. Tre atment of wild-type cells with tumor necrosis factor alpha (TNF-alpha) resulted in rapid, transient nuclear localization of NF-kappa B. I ka ppa B alpha-deficient fibroblasts are also TNF-alpha responsive, but n uclear localization of NF-kappa B is prolonged, thus demonstrating tha t a major irreplaceable function of I kappa B alpha is termination of the NF-kappa B response, Consistent with these observations, and with I kappa B alpha and NF-kappa B's role in regulating inflammatory and i mmune responses, is the normal development of I kappa B alpha-deficien t mice. However, growth ceases 3 days after birth and death usually oc curs at 7 to 10 days of age. An increased percentage of monocytes/macr ophages was detected in spleen cells taken from 5-, 7-, and 9-day-old pups, Death is accompanied by severe widespread dermatitis and increas ed levels of TNF-alpha mRNA in the skin.