Chapter category: Cytokines/Growth Factors
The Role of NF-AT and NF-kB Transcription
Chapter authors:
Edgar Serfling, Stefan Klein-Hessling, Ralf Marienfeld, Manfred Neumann, Thomas Twardzik and Andris Avots
Numerous sequence elements which control the inducible expression of the IL-2 gene in peripheral T lymphocytes are assembled in its immediate upstream DNA element of approximately 300 bp, the IL-2 promoter (see Refs. 1 and 2 for reviews). Although this relatively short DNA fragment does not comprise all sequence elements for the full expression of the endogenous IL-2 gene3,4 numerous functional studies have shown that the activity of the IL-2 promoter reflects in many aspects the expression of the chromosomal IL-2 gene, i.e., 1) the IL-2 promoter is transcriptionally inactive in nonstimulated T cells, 2) its activity is strongly induced after activation of T cells but not in other cells, such as in b cells, 3) it needs at least two signals for its activation, namely a rise of free intracellular Ca++ and the stimulation of Ras-involved protein kinase cascade(s), and, finally, 4) its induction can completely be inhibited by the immunosuppressants Cyclosporin A (CsA) and FK506 (see Ref. 2). Both immunosuppressants are efficient inhibitors of calcineurin, a Ca++/calmodulin-dependent phosphatase whose activity is crucially involved in the induction of IL-2 promoter activity and IL-2 expression in T cells.5,6
The structural organization of the IL-2 promoter is depicted in Fig. 1. The promoters of human and murine IL-2 genes share almost 87% sequence homology, and most of the functionally important sequence motifs have an identical structure. Therefore, the human IL-2 promoter can be induced efficiently when transfected into murine T cells (see Ref. 7 for the first characterization of the human IL-2 promoter) and, vice versa, the murine IL-2 promoter in human T cells. Functionally important sequence motifs are binding sites for transcription factors whose binding and activation leads to the assembly of a large transcription complex over the TATA box(es) and initiation site(s) of the gene. The binding of numerous transcripton factors to the human and murine IL-2 promoters has been demonstrated in a large number of DNA/protein studies, and a summary of these studies is compiled in Fig. 1.
