P50-NF-KAPPA-B 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 mul tiorgan inflammation and hematopoietic abnormalities. To examine wheth er other NF-kappa B/Rel family members are required for the developmen t of this phenotype or have a compensatory role, we have initiated a p rogram 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-kappa B (p50(-/-)). The infl ammatory phenotype of p50(-/-) relB(-/-) double-mutant mice was marked ly increased in both seventy and extent of organ involvement, leading to premature death within three to four weeks after birth. Double-knoc kout mice also had strongly increased myeloid hyperplasia and thymic a trophy. Moreover, B cell development was impaired and, in contrast to relB(-/-) single knockouts, B cells were absent from inflammatory infi ltrates. Both p50(-/-) and heterozygous relB(-/+) animals are disease- free. In the absence of the p50, however, relB(-/+) mice (p50(-/-) rel B(-/+)) had a mild inflammatory phenotype and moderate myeloid hyperpl asia. Neither elevated mRNA levels of other family members, nor increa sed kappa B-binding activities of NF-kappa B/Rel complexes could be de tected in single- or double-mutant mice compared to control animals. T hese results indicate that the lack of RelB is, in part, compensated b y other p50-containing complexes and that the ''classical'' p50-RelA-N F-kappa B activity is not required for the development of the inflamma tory phenotype.