title: p50-NF-kappaB complexes partially compensate for the absence of RelB: severely increased pathology in p50(-/-)relB(-/-) double-knockout mice.
abstract: RelB-deficient mice (relB(-/-)) have a complex phenotype including multiorgan inflammation and hematopoietic abnormalities. To examine whether other NF-kappaB/Rel family members are required for the development of this phenotype or have a compensatory role, we have initiated a program to generate double-mutant mice that are deficient in more than one family member. Here we report the phenotypic changes in relB(-/-) mice that also lack the p50 subunit of NF-kappaB (p50(-/-)). The inflammatory phenotype of p50(-/-)relB(-/-) double-mutant mice was markedly increased in both severity and extent of organ involvement, leading to premature death within three to four weeks after birth. Double-knockout mice also had strongly increased myeloid hyperplasia and thymic atrophy. Moreover, B cell development was impaired and, in contrast to relB(-/-) single knockouts, B cells were absent from inflammatory infiltrates. Both p50(-/-) and heterozygous relB(-/+) animals are disease-free. In the absence of the p50, however, relB(-/+) mice (p50(-/-)relB(-/+)) had a mild inflammatory phenotype and moderate myeloid hyperplasia. Neither elevated mRNA levels of other family members, nor increased kappaB-binding activities of NF-kappaB/Rel complexes could be detected in single- or double-mutant mice compared to control animals. These results indicate that the lack of RelB is, in part, compensated by other p50-containing complexes and that the "classical" p50-RelA-NF-kappaB activity is not required for the development of the inflammatory phenotype.
authors.affiliation: Department of Oncology, Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, New Jersey 08543-4000, USA.
authors.forename: F
authors.initials: F
authors.lastname: Weih
authors.forename: S K
authors.initials: SK
authors.lastname: Durham
authors.forename: D S
authors.initials: DS
authors.lastname: Barton
authors.forename: W C
authors.initials: WC
authors.lastname: Sha
authors.forename: D
authors.initials: D
authors.lastname: Baltimore
authors.forename: R
authors.initials: R
authors.lastname: Bravo
mesh_terms: D000015:Abnormalities, Multiple / Q000209:etiology / Q000401:mortality; D000818:Animals; D001853:Bone Marrow / Q000473:pathology; D004064:Digestive System / Q000473:pathology; D005786:Gene Expression Regulation; D007249:Inflammation; D008168:Lung / Q000473:pathology; D008214:Lymphocytes; D008221:Lymphoid Tissue / Q000473:pathology; D008264:Macrophages; D051379:Mice; D018345:Mice, Knockout; D009206:Myocardium / Q000473:pathology; D016328:NF-kappa B / Q000235:genetics*; D052002:NF-kappa B p50 Subunit; D010641:Phenotype; D011485:Protein Binding; D011518:Proto-Oncogene Proteins; D051841:Transcription Factor RelB; D014157:Transcription Factors / Q000235:genetics*
chemical_list: D016328:NF-kappa B; D052002:NF-kappa B p50 Subunit; D011518:Proto-Oncogene Proteins; C497594:Relb protein, mouse; D014157:Transcription Factors; D051841:Transcription Factor RelB