Role of two types of TNF receptors in activation of nuclear factor NF-κB, C-Jun N-terminal kinase and apoptosis

Tumor necrosis factor (TNF) is a multipotential cytokine that plays an important role in cell growth. viral replication. septic shock. inflammation and autoimmunity. Most of the effects of TNF are mediated through two different types of receptor, referred to as p60 (or type I) and p80 (or type II). The p60 receptor is expressed on all cell types whereas p80 is primarily expressed on immune cells. In vitro, within minutes TNF activates a nuclear transcription factor, NF-kB, and c-Jun N-terminal kinase (JNK). TNF also activates apoptosis of cells which usually requires several hours. The cytoplasmic domain (CD) of p60 receptor binds sequentially through its death domain (DD), to TRADD. FADD and RICE which leads to apoptosis: to TRADD and TRAF2 which leads to NF-kB and JNK activation. In comparison to p60 receptor, the CD of p80 receptor lacks DD and thus does not bind to TRADD. Inspire of these differences between the p60 and p80 receptors, we demonstrate by using receptor-specific muteins and receptor overexpression that both p60 and p80 receptor can activate apoptosis, JNK and NF-kB. The p80 receptor also potentiates the effect of p60 receptor.