Regulation of interleukin 4 gene transcription: alterations in atopic disease?

Abstract

Induction of interleukin 4 (IL-4) transcription in helper T (Th) cells under physiological conditions follows from engagement of the T cell receptor by antigenic peptides presented by antigen-presenting cells in association with MHC class II molecules (1). This trigger will activate two intracellular signaling pathways crucial to IL-4 expression, that is, a protein kinase C (PKC)-dependent pathway leading to the synthesis of activator protein 1 (AP-1) family proteins and a calcium (Ca 2 1 )dependent pathway resulting in calcineurin-mediated dephosphorylation and nuclear translocation of preexisting cytosolic nuclear factor of activated T cells (NFAT). The PKC pathway is potentiated by CD28-mediated costimulation (2), whereas the Ca 2 1 pathway can be fully blocked by cyclosporin A and FK506 (3). Both the mouse and human IL-4 promoters contain five binding elements (designated P0 to P4) for the NFAT family of transcription factors, with only minimal interspecies variation with respect to their sequence, orientation, and location within the proximal 250 base pairs (bp) of the promoter region (4–6). The P0 element is located just upstream of the transcription start site and P4 is located at about 2 250 bp in the 5 9 -flanking region (Figure 1). Although all P elements to some extent contribute to IL-4 gene control, the major positive regulatory P elements seem to be P1 (4, 7) and P4 (reviewed in Reference 1). As are P2 and P3, both P1 and P4 are immediately flanked by sequences with affinity for AP-1 family proteins (8–10), allowing for cooperative binding with NFAT proteins. The strong reduction of IL-4 promoter activity as observed, for example, after mutation of either the P1NFATor the adjacent AP-1-binding motif (9) emphasizes the importance of collaborative NFAT/AP-1 binding at such composite elements. The proximal part of the IL-4 promoter region, containing the transcription start site (indicated as 1 1 in Figure 1) and the P0 and P1 elements, can function as a minimal promoter in reporter gene assays, conferring inducible expression and a certain degree of Th2-specific regulation (11, 12). Initial studies gave no indication of Th1or Th2-specific recruitment of particular NFAT or AP-1 family proteins to these sites (9, 13). Instead, the mechanism underlying the Th2 specificity of IL-4 expression may be based on quantitative differences in the availability of NFAT and/or AP-1 family proteins. Furthermore, because the cooperative DNA binding of NFAT and AP-1 proteins has an auxiliary function for the binding of other transcription factors (5, 14–16), these additional transcription factors are likely to be involved in tissue-specific IL-4 expression. Th2-SPECIFIC IL-4 GENE CONTROL