| Proteolytic processing of the NF-kappaB2 precursor protein p100 generates the active NF-kappaB2 subunit p52, which in turn transcriptionally upregulates p100 expression. p100 also functions as an IkappaB molecule capable of repressing p52 activity. The biological significance of this negative feedback control loop has yet to be demonstrated. Here we show that mice deficient in p100 but with constitutive expression of p52 in lymphocyte developed fatal lung inflammation characterized by diffuse alveolar damage with perivascular and peribronchial fibrosis. This is in contrast to their p52-expressing littermates with wild-type p100 alleles, which developed mild lung inflammation with perivascular lymphocyte infiltration and had a normal life span. The fatal lung inflammation probably results from an ongoing T-helper-1 immune response, leading to high-level induction of IFN-lambda and its inducible inflammatory chemokines. These findings demonstrate the physiological relevance of the NF-kappaB2 p100 precursor protein in limiting the potentially detrimental effects of constitutive NF-kappaB2 signaling in lymphocytes.;NF-kappaB2 plays a crucial role in the lymphocytes and lymphoid organ development. Previous studies with NF-kappaB2-/- mice present a marked decrease in the peripheral B cell population, loss of inguinal lymph nodes, an absence of discrete perifollicular marginal and mantle zones, and of germinal centers in the spleen. Our analysis of the phenotypes of NF-kappaB2 p52-Tg mice with or without the NF-kappaB2 p100 precursor protein provides new insight into the role of NF-kappaB2 in the regulation of cell populations involved in periphery lymphoid organ development. We show that NF-kappaB2 p52 is responsible for the normal development of B cells which are essential for the formation of B-cell follicles, germinal centers, follicular dendritic cells networks and marginal zones in the spleen. These findings define a physiological function of NF-kappaB2 p52 in the development of the mouse immune system. |
