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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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Immunohistochemical  detection of T cells in lungs from  20-d-old wild-type, relB−/−,  and p50−/−relB−/− mice. (A–C )  Lung sections stained with an  mAb specific for CD4+ T helper  cells. (D–F ) Lung sections stained  with an mAb specific for CD8+  cytotoxic T cells. (A and D)  Wild-type control; (B and E )  relB−/− single mutant; (C and F )  p50−/−relB−/− double mutant.  Bars, 50 μm.
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Figure 3: Immunohistochemical detection of T cells in lungs from 20-d-old wild-type, relB−/−, and p50−/−relB−/− mice. (A–C ) Lung sections stained with an mAb specific for CD4+ T helper cells. (D–F ) Lung sections stained with an mAb specific for CD8+ cytotoxic T cells. (A and D) Wild-type control; (B and E ) relB−/− single mutant; (C and F ) p50−/−relB−/− double mutant. Bars, 50 μm.

Mentions: To examine the cellular composition of the inflammatory infiltrates in nonlymphoid tissues in more detail, lung and liver sections from 20-d-old wildtype controls, relB−/−, and p50−/−relB−/− mice were analyzed by immunohistochemical criteria. Only resident leukocyte populations were detected in control tissues stained with the different mAbs (Fig. 3, A and D; and Fig. 4, A, D, and G). In contrast, abundant staining was observed in pulmonary infiltrates of both relB−/− and p50−/−relB−/− mice with mAbs specific for CD4+ helper T cells (Fig. 3, B and C ) and CD8+ cytotoxic T cells, although a smaller number of CD8+ lymphocytes occurred both quantitatively and proportionally in the infiltrates of double-knockout mice (Fig. 3 E and F). Prominent infiltrates, consisting predominantly of CD4+ and CD8+ lymphocytes, were observed in the lung and liver of these animals as early as 10 d after birth, suggesting that T cells are crucially involved in the onset of the inflammatory phenotype (data not shown).


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)

Immunohistochemical  detection of T cells in lungs from  20-d-old wild-type, relB−/−,  and p50−/−relB−/− mice. (A–C )  Lung sections stained with an  mAb specific for CD4+ T helper  cells. (D–F ) Lung sections stained  with an mAb specific for CD8+  cytotoxic T cells. (A and D)  Wild-type control; (B and E )  relB−/− single mutant; (C and F )  p50−/−relB−/− double mutant.  Bars, 50 μm.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2196264&req=5

Figure 3: Immunohistochemical detection of T cells in lungs from 20-d-old wild-type, relB−/−, and p50−/−relB−/− mice. (A–C ) Lung sections stained with an mAb specific for CD4+ T helper cells. (D–F ) Lung sections stained with an mAb specific for CD8+ cytotoxic T cells. (A and D) Wild-type control; (B and E ) relB−/− single mutant; (C and F ) p50−/−relB−/− double mutant. Bars, 50 μm.
Mentions: To examine the cellular composition of the inflammatory infiltrates in nonlymphoid tissues in more detail, lung and liver sections from 20-d-old wildtype controls, relB−/−, and p50−/−relB−/− mice were analyzed by immunohistochemical criteria. Only resident leukocyte populations were detected in control tissues stained with the different mAbs (Fig. 3, A and D; and Fig. 4, A, D, and G). In contrast, abundant staining was observed in pulmonary infiltrates of both relB−/− and p50−/−relB−/− mice with mAbs specific for CD4+ helper T cells (Fig. 3, B and C ) and CD8+ cytotoxic T cells, although a smaller number of CD8+ lymphocytes occurred both quantitatively and proportionally in the infiltrates of double-knockout mice (Fig. 3 E and F). Prominent infiltrates, consisting predominantly of CD4+ and CD8+ lymphocytes, were observed in the lung and liver of these animals as early as 10 d after birth, suggesting that T cells are crucially involved in the onset of the inflammatory phenotype (data not shown).

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