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

Abstract

The ubiquitous transcription factor NF-B is an essential component in signal transduction pathways, in inflammation, and in the immune response. NF-B is maintained in an inactive state in the cytoplasm by protein-protein interaction with IB␣. Upon stimulation, rapid degradation of IB␣ allows nuclear translocation of NF-B. To study the importance of IB␣ in signal transduction, IB␣-deficient mice were derived by gene targeting. Cultured fibroblasts derived from IB␣-deficient embryos exhibit levels of NF-B1, NF-B2, RelA, c-Rel, and IB␤ similar to those of wild-type fibroblasts. A failure to increase nuclear levels of NF-B indicates that cytoplasmic retention of NF-B may be compensated for by other IB proteins. Treatment of wild-type cells with tumor necrosis factor alpha (TNF-␣) resulted in rapid, transient nuclear localization of NF-B. IB␣-deficient fibroblasts are also TNF-␣ responsive, but nuclear localization of NF-B is prolonged, thus demonstrating that a major irreplaceable function of IB␣ is termination of the NF-B response. Consistent with these observations, and with IB␣ and NF-B's role in regulating inflammatory and immune responses, is the normal development of IB␣-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-␣ mRNA in the skin.Members of the Rel transcription factor family regulate the expression of numerous genes, including many of those involved in immune and inflammatory responses (for reviews, see references 4, 22, and 54). The known mammalian Rel proteins-NF-B1 (p50/p105), NF-B2 (p52/p100), RelA (p65), c-Rel, and RelB-contain a conserved 300-amino-acid Rel-homology domain, which is involved in protein-protein interaction, DNA binding, and nuclear localization. Nearly all possible homodimers and heterodimers have been observed (classical NF-B is a heterodimer of p50 and p65). These dimers are capable of binding to the B DNA binding site-a 10-or 11 bp sequence that conforms to a loose consensus. Rel proteins are expressed in most (perhaps all) cells, although their individual levels may vary with the cell type. With few exceptions, the various dimers are localized in the cytoplasm of unstimulated cells. A wide variety of agents (e.g., phorbol ester, lipopolysaccharide [LPS], and cytokines) induce the nuclear translocation of Rel proteins, initiating expression of numerous genes.Rel dimers are held in the cytoplasm by members of the IB family of inhibitor proteins, all of which contain five to seven copies of the ''ankyrin repeat''-a 33-amino-acid motif that is particularly abundant in the protein ankyrin. The inhibitor IB␣ is capable of binding to most (perhaps all) dimers, thereby blocking their nuclear localization signals (6,20,34). Upon stimulation of the cell, IB␣ undergoes phosphorylation and rapid degradation (5,9,16,26,41,57), resulting ...

Prevention and regression of atopic dermatitis by ointment containing NF-kB decoy oligodeoxynucleotides in NC/Nga atopic mouse model

“…24 More recently, the importance of NFkB was proved by the observation that IkB␣ deficiency resulted in a sustained NF-kB response and severe widespread dermatitis in mice. 25 In addition, the skin of RelBdeficient mice develops T cell-dependent skin lesions similar to human atopic dermatitis, 26 correlating with induced p50-RelA/NF-kB activity due to IkB␣ stability. 27 These reports support the efficacy of NF-kB decoy ODN to treat atopic dermatitis.…”

Anti-inflammatory functions of glucocorticoid-induced genes

“…Mice lacking IκBα have a severe inflammatory phenotype and die soon after birth (Beg et al, 1995;Chen et al, 2000;Klement et al, 1996), which is likely to complicate experiments to directly address the role of IκBα in responses to GCs. The question might be best answered by studying GC responses in conditional and/or tissue-specific IκBα knockouts.…”

Genetic approaches in mice to understand Rel/NF-κB and IκB function: transgenics and knockouts

“…Although the embryonic development of mice lacking IkBa appears to be normal, ikba 7/7 mice die 7 ± 10 days post-natally, a icted by severe widespread inflammatory dermitis and granulocytosis (Beg et al, 1995;Klement et al, 1996). Coincident with this phenotype, the expression of certain proin¯ammatory cytokines and factors associated with granulocyte recruitment, adherence and activation such as TNFa, G-CSF, MIP-2 and VCAM-1 is increased.…”