Chronic Inflammation and Susceptibility to Bacterial Infections in Mice Lacking the Polypeptide (p)105 Precursor (NF-κB1) but Expressing p50

Abstract

The polypeptide (p)50 molecule, a subunit of nuclear factor (NF)-κB, is produced after proteolytic processing of the p105 precursor (NF-κB1). Although the p105 precursor has been postulated to play a role in the regulation of the Rel/NF-κB activity, its physiological relevance remains unclear. To investigate that, we generated mutant mice lacking the COOH terminal half of the p105 precursor, but expressing the p50 product (p105−/−). These mutant mice displayed an inflammatory phenotype composed of lymphocytic infiltration in lungs and liver, and an increased susceptibility to opportunistic infections. Enlargement of multiple lymph nodes, splenomegaly due to erythrocytic extramedullary hematopoiesis, and lymphoid hyperplasia were also observed in p105−/− mice. Cytokine production in p105−/− macrophages was severely impaired, whereas proliferative responses of p105−/− B cells were increased. T cell functions were only moderately impaired in mutant mice. Loss of p105 also led to enhanced constitutive p50 homodimer and inducible NF-κB activities in unstimulated and stimulated cells, respectively. As several genes regulated by Rel/NF-κB were upregulated in p105−/− thymus but downregulated in p105−/− macrophages, the enhanced p50 homodimers appear to function as transcriptional activators or repressors, depending on the cell type. Thus, the p105 precursor is indispensable in the control of p50 activity, and lack of the precursor has distinct effects on different cells.

Unravelling the complexities of the NF-κB signalling pathway using mouse knockout and transgenic models

“…nfkb2 DCT/DCT mice. Like the nfkb1 DCT/DCT mice (Ishikawa et al, 1998), targeted deletion of the p100 C-terminal ankyrin repeats reveals their importance as an inhibitory domain. Mice homozygous for this C-terminal deletion (nfkb2 DCT/DCT ) develop a wide range of postnatal pathologies that include gastric hyperplasia, hyperkeratosis in the heart and spleen, lymphocytic infiltrates of various tissues, enlarged lymph nodes and granulocytosis (Ishikawa et al, 1997).…”

“…Targeted deletion of the p105 C-terminal ankyrin repeats, which leads to elevated levels of nuclear p50 homodimers, confirms the importance of the C terminus as a regulatory domain. Animals homozygous for this mutation (nfkb1 DCT/DCT ) exhibit splenomegaly, enlarged lymph nodes and lymphoid infiltrates in various organs (Ishikawa et al, 1998). An increase in the number of B cells is accompanied by hyperresponsiveness to mitogens.…”

The prognostic impact of NF-κB p105, vimentin, E-cadherin and Par6 expression in epithelial and stromal compartment in non-small-cell lung cancer

“…Havard et al (2005) observed high levels of NF-kB p105 precursor in cell lines derived from human cervical cancers associated with HPV16 infection and in keratinocytes transfected by oncogenes. In another study, Ishikawa et al (1998) observed that NF-kB p105À/À mice showed abnormalities such as inflammation in lungs and liver, myeloid hyperplasia in bone marrow and splenomegaly (Weih et al, 1994). In a study that included 45 patients with NSCLC, Zhang et al (2006) found overexpression of NF-kB p50 to indicate an unfavourable overall survival in NSCLC patients.…”

BCL-6 Negatively Regulates Expression of the NF-κB1 p105/p50 Subunit

“…For example, Ishikawa et al (46) studied a mouse model in which the genetically engineered NF-B1 locus directly produces the mature p50 subunit instead of the p105 precursor. In these animals, a dramatic increase in the nuclear p50 homodimer was observed, and yet expression of a number of NF-B target genes, including CSF-1, actually increased.…”