Biphasic control of nuclear factor‐χB activation by the T cell receptor complex: role of tumor necrosis factor α

摘要

AbstractThe regulation of nuclear factor (NF)‐χB activation by the T cell receptor (TcR)/CD3 complex in primary human T cells has been studied at various times after activation. Only p50 NF‐χB protein bound the χB element of interleukin‐2 receptor (IL‐2R) α chain promoter on resting T cells. However, immediately after TcR/CD3 cross‐linking (after approximately 1 h; immediate) binding of p50.p65 heterodimers was observed. p50.c‐rel heterodimers were also detected bound to this sequence at early time points (7–16 h; early), and both remained active at later time points (40 h; late) after activation. This regulation takes place mainly at the level of nuclear translocation of p65 and c‐rel, at immediate and early time points. Activation also induced c‐rel and p105/p50 mRNA synthesis, but not p65 mRNA whose expression was constitutive. Interestingly, all those early and late events, but not the immediate ones, were inhibited by a neutralizing anti‐tumor necrosis factor α (TNF‐α) monoclonal antibody. Similarly, cycloheximide prevented the p65 and c‐rel translocation and consequent formation of active binding heterodimers, at early and late times. Cyclosporin A impaired not only early and late, but also immediate events; however, addition of TNF‐α prevented all inhibition. These results indicate that the regulation of NF‐χB activation during T cell activation by TcR/CD3 signals is biphasic: TcR/CD3 triggers its immediate translocation, which is transient if no TNF‐α is present. TNF‐α, therefore, emerges as the main factor responsible for a second phase of NF‐χB regulation, controlling both translocation of p65 and c‐rel,