Proteolytic processing of the nuclear factor (NF)-kappaB2 precursor protein p100 
generates the active NF-kappaB2 subunit p52, which in turn transcriptionally 
up-regulates 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 in vivo. Here we show that mice 
deficient in p100 but with constitutive expression of p52 in lymphocytes 
developed fatal lung inflammation characterized by diffuse alveolar damage with 
marked peribronchial fibrosis. In contrast, their littermates with only p100 
deficiency or constitutive expression of p52 in lymphocytes developed mild lung 
inflammation with perivascular lymphocyte infiltration and had a normal life 
span. The fatal lung inflammation is associated with high-level induction of 
interferon-gamma and its inducible inflammatory chemokines, suggesting the 
involvement of a T-helper-1 immune response. 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.