Constitutive production of NF-kappaB2 p52 is not tumorigenic but predisposes mice to inflammatory autoimmune disease by repressing Bim expression.
Normal development of the immune system requires regulated processing of NF-kappaB2 p100 to p52, which activates NF-kappaB2 signaling. Constitutive production of p52 has been suggested as a major mechanism underlying lymphomagenesis induced by NF-kappaB2 mutations, which occur recurrently in a variety of human lymphoid malignancies. To test the hypothesis, we generated transgenic mice with targeted expression of p52 in lymphocytes. In contrast to their counterparts expressing the tumor-derived NF-kappaB2 mutant p80HT, which develop predominantly B cell tumors, p52 transgenic mice are not prone to lymphomagenesis. However, they are predisposed to inflammatory autoimmune disease characterized by multiorgan infiltration of activated lymphocytes, high levels of autoantibodies in the serum, and immune complex glomerulonephritis. p52, but not p80HT, represses Bim expression, leading to defects in apoptotic processes critical for elimination of autoreactive lymphocytes and control of immune response. These findings reveal distinct signaling pathways for actions of NF-kappaB2 mutants and p52 and suggest a causal role for sustained NF-kappaB2 activation in the pathogenesis of autoimmunity.
Wang
Zhe
Z
Department of Biochemistry and Cancer Biology, College of Medicine, University of Toledo Health Science Campus, Toledo, Ohio 43614, USA.
Zhang
Baochun
B
Yang
Liqun
L
Ding
Jane
J
Ding
Han-Fei
HF
D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism / Q000502:physiology*; D001323:Autoantibodies / Q000737:chemistry; D000072224:Bcl-2-Like Protein 11; D005786:Gene Expression Regulation; D020022:Genetic Predisposition to Disease; D006801:Humans; D007249:Inflammation; D008214:Lymphocytes / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009154:Mutation; D052003:NF-kappa B p52 Subunit / Q000096:biosynthesis*; D011518:Proto-Oncogene Proteins / Q000378:metabolism / Q000502:physiology*; D015398:Signal Transduction; D013154:Spleen / Q000166:cytology / Q000378:metabolism
D051017:Apoptosis Regulatory Proteins; D001323:Autoantibodies; C000606775:BCL2L11 protein, human; D000072224:Bcl-2-Like Protein 11; C000606776:Bcl2l11 protein, mouse; D008565:Membrane Proteins; D052003:NF-kappa B p52 Subunit; D011518:Proto-Oncogene Proteins