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

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  • Falk Weih
    From the *Department of Oncology, ‡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
  • Stephen K. Durham
    From the *Department of Oncology, ‡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
  • Debra S. Barton
    From the *Department of Oncology, ‡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
  • William C. Sha
    From the *Department of Oncology, ‡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
  • David Baltimore
    From the *Department of Oncology, ‡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
  • Rodrigo Bravo
    From the *Department of Oncology, ‡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

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<jats:p>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.</jats:p>

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