INVOLVEMENT OF EGR-1 RELA SYNERGY IN DISTINGUISHING T-CELL ACTIVATIONFROM TUMOR NECROSIS FACTOR-ALPHA-INDUCED NF-KAPPA-B1 TRANSCRIPTION/

NF-kappa B is an important transcription factor required for T cell pr oliferation and other immunological functions. The NF-kappa B1 gene en codes a 105-kD protein that is the precursor of the p50 component of N F-kappa B. Previously, we and others have demonstrated that NF-kappa B regulates the NF-kappa B1 gene. In this manuscript we have investigat ed the molecular mechanisms by which T cell lines stimulated with phor bol 12-myristate 13-acetate (PMA) and phytohemagglutin (PHA) display s ignificantly higher levels of NF-kappa B1 encoding transcripts than ce lls stimulated with tumor necrosis factor-alpha, despite the fact that both stimuli activate NF-kappa B. Characterization of the NF-kappa B1 promoter identified an Egr-1 site which was found to be essential for both the PMA/PHA-mediated induction as well as the synergistic activa tion observed after the expression of the RelA subunit of NF-kappa B a nd Egr-1. Furthermore, Egr-1 induction was required for endogenous NF- kappa B1 gene expression, since PMA/PHA-stimulated T cell lines expres sing antisense Egr-1 RNA were inhibited in their ability to upregulate NF-kappa B1 transcription. Our studies indicate that transcriptional synergy mediated by activation of both Egr-1 and NF-kappa B may have i mportant ramifications in T cell development by upregulating NF-kappa B1 gene expression.