Biphasic control of nuclear factor-kappa B activation by the T cell receptor complex: role of tumor necrosis factor alpha

Eur J Immunol. 1995 Jan;25(1):179-86. doi: 10.1002/eji.1830250130.


The regulation of nuclear factor (NF)-kappa B 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-kappa B protein bound the kappa B element of interleukin-2 receptor (IL-2R) alpha 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 alpha (TNF-alpha) 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-alpha prevented all inhibition. These results indicate that the regulation of NF-kappa B activation during T cell activation by TcR/CD3 signals is biphasic: TcR/CD3 triggers its immediate translocation, which is transient if no TNF-alpha is present. TNF-alpha, therefore, emerges as the main factor responsible for a second phase of NF-kappa B regulation, controlling both translocation of p65 and c-rel, and new mRNA synthesis for c-rel and p105/p50.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antibodies, Monoclonal
  • Base Sequence
  • Blotting, Northern
  • Blotting, Western
  • Cells, Cultured
  • Cycloheximide / pharmacology
  • Cyclosporine / pharmacology
  • Electrophoresis, Polyacrylamide Gel / methods
  • Humans
  • Molecular Sequence Data
  • NF-kappa B / biosynthesis*
  • Receptor-CD3 Complex, Antigen, T-Cell / immunology*
  • T-Lymphocytes / drug effects
  • T-Lymphocytes / immunology*
  • Tumor Necrosis Factor-alpha / immunology*


  • Antibodies, Monoclonal
  • NF-kappa B
  • Receptor-CD3 Complex, Antigen, T-Cell
  • Tumor Necrosis Factor-alpha
  • Cyclosporine
  • Cycloheximide