CHRONIC INFLAMMATION AND SUSCEPTIBILITY TO BACTERIAL-INFECTIONS IN MICE LACKING THE POLYPEPTIDE (P)105 PRECURSOR (NF-KAPPA-B1) BUT EXPRESSING P50

The polypeptide (p)50 molecule, a subunit of nuclear factor (NF)-kappa B, is produced after proteolytic processing of the p105 precursor (NF -kappa B1). Although the p105 precursor has been postulated to play a role in the regulation of the Rel/NF-kappa B activity, its physiologic al relevance remains unclear. To investigate that, we generated mutant mice lacking the COOH terminal half of the p105 precursor, but expres sing the p50 product (p105(-/-)). These mutant mice displayed an infla mmatory phenotype composed of lymphocytic infiltration in lungs and li ver, and an increased susceptibility to opportunistic infections. Enla rgement of multiple lymph nodes, splenomegaly due to erythrocytic extr amedullary hematopoiesis, and lymphoid hyperplasia were also observed in p105(-/-) mice. Cytokine production in p105(-/-) macrophages was se verely impaired, whereas proliferative responses of p105(-/-) B cells were increased. T cell functions were only moderately impaired in muta nt mice. Loss of p105 also led to enhanced constitutive p50 homodimer and inducible NF-kappa B activities in unstimulated and stimulated cel ls, respectively. As several genes regulated by Rel/NF-kappa B were up regulated in p105(-/-) thymus but downregulated in p105(-/-) macrophag es, the enhanced p50 homodimers appear to function as transcriptional activators or repressors, defending on the cell type. Thus, the p105 p recursor is indispensable in the control of p50 activity, and lack of the precursor has distinct effects on different cells.