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p50-NF-kappaB complexes partially compensate for the absence of RelB: severely increased pathology in p50(-/-)relB(-/-) double-knockout mice.

Weih F, Durham SK, Barton DS, Sha WC, Baltimore D, Bravo R - J. Exp. Med. (1997)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Oncology, Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, New Jersey 08543-4000, USA.

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.

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Flow cytometric analysis of 3-wk-old p50−/−, p50−/−relB−/+,  and p50−/−relB−/− mice. Thymus (A), spleen (B), and bone marrow (C )  single cell suspensions were analyzed for surface expression of CD4, CD8,  and TCR-α/β (T cells), B220 and IgM (B cells), Mac-1 (macrophages  and granulocytes), and Gr-1 (granulocytes). Genotypes are depicted above  representative plots. Numbers indicate subpopulation percentages.
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Figure 5: Flow cytometric analysis of 3-wk-old p50−/−, p50−/−relB−/+, and p50−/−relB−/− mice. Thymus (A), spleen (B), and bone marrow (C ) single cell suspensions were analyzed for surface expression of CD4, CD8, and TCR-α/β (T cells), B220 and IgM (B cells), Mac-1 (macrophages and granulocytes), and Gr-1 (granulocytes). Genotypes are depicted above representative plots. Numbers indicate subpopulation percentages.

Mentions: Flow cytometric analysis of 3-wk-old p50−/−relB−/− double-knockout mice revealed marked alterations in thymus, spleen, and bone marrow cell subpopulations. Mice deficient in the p50 subunit of NFκB, like heterozygous relB−/+ mice, do not have any changes compared to wild-type animals (8, 21; data not shown) and were used as controls. We also included relB−/+ mice on a p50−/− background (p50−/−relB−/+) since these animals develop a mild inflammatory phenotype (see Table 1). CD4+CD8+ double positive (DP) TCRlo thymocytes were dramatically reduced in double knockouts, whereas CD8+ and, in particular, CD4+ single positive TCRhi T cells were relatively increased (Fig. 5 A). Mature T cells were present in p50−/−relB−/− spleen whereas B220+IgM+ B cells were markedly reduced. In contrast, numbers of myeloid cells (Mac-1+, Gr-1+, 7/4+) were dramatically increased (Fig. 5 B and data not shown). With respect to the reduced number of B cells, p50−/−relB−/− double-knockout spleens were characterized by poorly-developed B cell follicles, hyperplastic periarterial lymphatic sheath (T cell) areas, and indiscrete marginal zones (data not shown). Flow cytometric analysis of bone marrow cells also revealed increased numbers of myeloid cells and markedly reduced B220+ IgM− and B220+IgM+ B cell populations (Fig. 5 C). Interestingly, p50−/−relB−/+ mice also had a moderate reduction in splenic B cells and increased numbers of myeloid cells in the bone marrow, but normal T cell subsets in thymus and spleen (Fig. 5, A–C).


p50-NF-kappaB complexes partially compensate for the absence of RelB: severely increased pathology in p50(-/-)relB(-/-) double-knockout mice.

Weih F, Durham SK, Barton DS, Sha WC, Baltimore D, Bravo R - J. Exp. Med. (1997)

Flow cytometric analysis of 3-wk-old p50−/−, p50−/−relB−/+,  and p50−/−relB−/− mice. Thymus (A), spleen (B), and bone marrow (C )  single cell suspensions were analyzed for surface expression of CD4, CD8,  and TCR-α/β (T cells), B220 and IgM (B cells), Mac-1 (macrophages  and granulocytes), and Gr-1 (granulocytes). Genotypes are depicted above  representative plots. Numbers indicate subpopulation percentages.
© Copyright Policy
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC2196264&req=5

Figure 5: Flow cytometric analysis of 3-wk-old p50−/−, p50−/−relB−/+, and p50−/−relB−/− mice. Thymus (A), spleen (B), and bone marrow (C ) single cell suspensions were analyzed for surface expression of CD4, CD8, and TCR-α/β (T cells), B220 and IgM (B cells), Mac-1 (macrophages and granulocytes), and Gr-1 (granulocytes). Genotypes are depicted above representative plots. Numbers indicate subpopulation percentages.
Mentions: Flow cytometric analysis of 3-wk-old p50−/−relB−/− double-knockout mice revealed marked alterations in thymus, spleen, and bone marrow cell subpopulations. Mice deficient in the p50 subunit of NFκB, like heterozygous relB−/+ mice, do not have any changes compared to wild-type animals (8, 21; data not shown) and were used as controls. We also included relB−/+ mice on a p50−/− background (p50−/−relB−/+) since these animals develop a mild inflammatory phenotype (see Table 1). CD4+CD8+ double positive (DP) TCRlo thymocytes were dramatically reduced in double knockouts, whereas CD8+ and, in particular, CD4+ single positive TCRhi T cells were relatively increased (Fig. 5 A). Mature T cells were present in p50−/−relB−/− spleen whereas B220+IgM+ B cells were markedly reduced. In contrast, numbers of myeloid cells (Mac-1+, Gr-1+, 7/4+) were dramatically increased (Fig. 5 B and data not shown). With respect to the reduced number of B cells, p50−/−relB−/− double-knockout spleens were characterized by poorly-developed B cell follicles, hyperplastic periarterial lymphatic sheath (T cell) areas, and indiscrete marginal zones (data not shown). Flow cytometric analysis of bone marrow cells also revealed increased numbers of myeloid cells and markedly reduced B220+ IgM− and B220+IgM+ B cell populations (Fig. 5 C). Interestingly, p50−/−relB−/+ mice also had a moderate reduction in splenic B cells and increased numbers of myeloid cells in the bone marrow, but normal T cell subsets in thymus and spleen (Fig. 5, A–C).

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Oncology, Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, New Jersey 08543-4000, USA.

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.

Show MeSH
Related in: MedlinePlus