p50–NF-κB Complexes Partially Compensate for the Absence of RelB: Severely Increased Pathology in p50(−) (/−) relB(−) (/−)Double-knockout Mice

RelB-deficient mice (relB(−) (/−)) have a complex phenotype including multiorgan inflammation and hematopoietic abnormalities. To examine whether other NF-κB/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 NFκB (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 κB-binding activities of NF-κB/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-κB activity is not required for the development of the inflammatory phenotype.