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© The Rockefeller University Press, 0022-1007/1997/4/1359/ $5.00
The Journal of Experimental Medicine, Volume 185, Number 7, April 7, 1997 1359-1370

Article

p50–NF-{kappa}B Complexes Partially Compensate for the Absence of RelB: Severely Increased Pathology in p50–/–relB–/–Double-knockout Mice

Falk Weih*, Stephen K. Durham{ddagger}, Debra S. Barton{ddagger}, William C. Sha§, David Baltimore§, and Rodrigo Bravo*

From the * Department of Oncology, {ddagger} Department of Experimental Pathology, Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, New Jersey 08543-4000; and the § Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139

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

Address correspondence to Rodrigo Bravo, Department of Oncology, Bristol-Myers Squibb Pharmaceutical Research Institute, PO Box 4000, Princeton, NJ 08543-4000. The present address of W.C. Sha is Department of Molecular and Cell Biology, University of California at Berkeley, Berkeley, CA 94720-3200.

1Abbreviations used in this paper: DC, dendritic cells; DOC, deoxycholate; DP, double positive; EMSA, electrophoretic mobility shift assays.


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