Dissecting the Biological Function of NF‐¿B2p100

Abstract

Nuclear Factor‐kappaB2 (NF‐¿B2), a member of the NF‐¿B family of transcription factors, has an important role in the development and function of the immune system. It is synthesized as a protein of 100‐kDa (p100). In response to certain cytokines, p100 undergoes proteolytic processing, leading to the generation of p52 that corresponds to the N‐terminal half of p100. p52 functions as a transcription activator with anti‐apoptotic activity; constitutive activation of p52 can lead to autoimmune inflammation. Previous in vitro studies have provided evidence that, in addition to serving as a precursor for p52, p100 functions as an I¿B molecule with the ability to restrain p52 activity. However, the physiological relevance of this I¿B activity of p100 has never been demonstrated. To address the question, I have generated p52 transgenic mouse lines with or without NF‐¿B2 p100. Compared to p52 transgenic mice carrying wild‐type p100 alleles, p52 mice deficient in NF‐¿B2 p100 show a marked increase in the mortality rate with severe inflammation in the lung, characterized by extensive infiltrations of lymphocytes and macrophages. Lymphocytes from these mice contain significantly higher levels of ¿B‐binding activity. These data demonstrate the function of p100 as a mechanism to limit the activity of p52, which has important implications in clinical control of inflammation.Supported by NCI Grant R01 CA106550 (to H.‐F. D.).