TUMOR-NECROSIS-FACTOR-ALPHA, INTERLEUKIN-1, AND PHORBOL-MYRISTATE ACETATE ARE INDEPENDENT ACTIVATORS OF NF-KAPPA-B WHICH DIFFERENTIALLY ACTIVATE T-CELLS

Gene expression in eukaryotic cells can be altered in different ways by extracellular agents, including mitogens and cytokines. Such differential gene expression is mediated in part through the effects of these stimuli on distinct sets of cellular transcription factors. In this report, the effects of phorbol myristate acetate, tumor necrosis factor-α (TNF-α), and interleukin 1 (IL-1) on differential gene expression in the LBRM mouse T-lymphoma cell line are examined. Although these three different stimuli produce similar levels of induction of the NF-κB transcription factor, it is reported that they cause differential expression of other cellular activation genes, including c-fos and IL-2. The roles of IL-1 and TNF-α were also analyzed in EL-4 cells in the presence of a second activator, ionomycin. IL-1, but not TNF-α, was found to stimulate the IL-2 enhancer in the presence of this costimulator. These findings suggest that one transcription factor can be the target of cellular activators that exert otherwise different effects on gene expression. Cellular activation pathways can therefore be defined by the set of transcription factors stimulated within a cell. This approach may allow a more precise definition of the requirements for differential gene activation in different cell types and thereby provide a basis for the selective manipulation of gene expression in cytokine-responsive cells. © 1991.