IkappaBalpha/IkappaBepsilon deficiency reveals that a critical NF-kappaB dosage is required for lymphocyte survival.
In most cells, the NF-kappaB transcription factor is sequestered in the cytoplasm by interaction with inhibitory proteins, the IkappaBs. Here, we show that combined IkappaBalpha/IkappaBepsilon deficiency in mice leads to neonatal death, elevated kappaB binding activity, overexpression of NF-kappaB target genes, and disruption of lymphocyte production. In IkappaBalpha/IkappaBepsilon-deficient fetuses, B220+IgM+ B cells and single-positive T cells die by apoptosis. In adults, IkappaBalpha-/-IkappaBepsilon-/- reconstituted chimeras exhibit a nearly complete absence of T and B cells that is not rescued by cotransfer with wild-type bone marrow. These findings demonstrate that IkappaBs tightly control NF-kappaB activity in vivo and that increased NF-kappaB activity intrinsically impairs lymphocyte survival. Because reduction or rise of NF-kappaB activity leads to similar dysfunction, they also reveal that only a narrow window of NF-kappaB activity is tolerated by lymphocytes.
Goudeau
Bertrand
B
Unité de Biologie Moléculaire de l'Expression Génique, Unité de Recherche Associée, Centre National de la Recherche Scientifique 2582, Unité de Biologie Moléculaire du Gène, Paris Cedex 15, France.
Huetz
François
F
Samson
Sandrine
S
Di Santo
James P
JP
Cumano
Ana
A
Beg
Amer
A
Israël
Alain
A
Mémet
Sylvie
S
D000818:Animals; D001483:Base Sequence; D002470:Cell Survival; D015321:Gene Rearrangement / Q000276:immunology; D020672:I-kappa B Proteins / Q000235:genetics / Q000502:physiology*; D007143:Immunoglobulin Heavy Chains / Q000235:genetics; D007147:Immunoglobulin Light Chains / Q000235:genetics; D008214:Lymphocytes / Q000166:cytology / Q000276:immunology*; D051379:Mice; D018345:Mice, Knockout; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000378:metabolism*; D015345:Oligonucleotide Probes; D016133:Polymerase Chain Reaction; D011518:Proto-Oncogene Proteins / Q000172:deficiency* / Q000235:genetics / Q000502:physiology*
D020672:I-kappa B Proteins; D007143:Immunoglobulin Heavy Chains; D007147:Immunoglobulin Light Chains; D016328:NF-kappa B; C000606205:Nfkbia protein, mouse; C491366:Nfkbie protein, mouse; D015345:Oligonucleotide Probes; D011518:Proto-Oncogene Proteins; D000072000:NF-KappaB Inhibitor alpha