Constitutive Production of NF-κB2 p52 Is Not Tumorigenic but Predisposes Mice to Inflammatory Autoimmune Disease by Repressing Bim Expression

Zhe Wang,Baochun Zhang,Liqun Yang,Jane Ding,Han-Fei Ding

doi:10.1074/jbc.m800806200

Abstract

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.

Highlights

These findings demonstrate that NF-␬B2 mutation can directly induce lymphomagenesis, with TRAF1 as a key component of this oncogenic pathway [22]
We present genetic evidence that constitutive production of p52 is not a major mechanism for the tumorigenic activity of NF-␬B2 mutants
P52 transgenic mice are highly susceptible to the development of inflammatory autoimmune disease

Summary

Introduction

We isolated infiltrating cells from the lungs of p52 mice (n ϭ 6) and performed flow cytometry analysis for the frequency of activated lymphocytes (Fig. 2D). Consistent with the increased sizes of lymphoid organs, flow cytometry analysis revealed that p52 mice had a significant increase in numbers of total splenic B (36%) and T cells (44%) (Fig. 5B), demonstrating that constitutive production of p52 promoted expansion of splenic lymphocyte populations.

Results

Conclusion