Loss of negative feedback control of nuclear factor-kappaB2 activity in lymphocytes leads to fatal lung inflammation.
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.
Yang
Liqun
L
Department of Biochemistry and Cancer Biology, University of Toledo Health Science Campus, Toledo, Ohio, USA.
Cui
Hongjuan
H
Wang
Zhe
Z
Zhang
Baochun
B
Ding
Jane
J
Liu
Lin
L
Ding
Han-Fei
HF
D000818:Animals; D002460:Cell Line; D018925:Chemokines / Q000276:immunology; D025461:Feedback, Physiological / Q000502:physiology*; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D006801:Humans; D007371:Interferon-gamma / Q000276:immunology; D008168:Lung / Q000166:cytology / Q000276:immunology* / Q000473:pathology; D008171:Lung Diseases / Q000276:immunology / Q000401:mortality / Q000473:pathology; D008214:Lymphocytes / Q000166:cytology / Q000378:metabolism*; D008264:Macrophages / Q000166:cytology / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D052003:NF-kappa B p52 Subunit / Q000235:genetics / Q000378:metabolism*; D011498:Protein Precursors / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D015996:Survival Rate
D018925:Chemokines; D052003:NF-kappa B p52 Subunit; D011498:Protein Precursors; D007371:Interferon-gamma