Positive and negative regulation of IL-2 gene expression: Role of multiple regulatory sites

Abstract

Interleukin 2 (IL-2) is an important lymphokine required in the process of T cell activation, proliferation, clonal expansion and differentiation. The IL-2 gene displays both T cell specific and inducible expression: it is only expressed in CD4 + T cells after antigenic or mitogenic stimulation. Several cis-acting regulatory sites are required for induction of the IL-2 gene after stimulation. In this study, we have analysed the function of these cis-acting regulatory sites in the context of the native IL-2 enhancer and promoter sequence. The results of this study suggest that the NFAT (−276 to −261), the distal octamer (−256 to −248) and the proximal octamer (−75 to −66) sites not only act as enhancers of IL-2 gene transcription in the presence of cellular stimulation, but also have a silencing effect on IL-2 gene expression in resting cells. Two other sites display disparate effects on IL-2 gene expression in different T leukemia cell lines: the distal purine box (−291 to −277) and the proximal purine box sites (−145 to −128). Finally, the AP-1 (−186 to −176) and the κB sites (−206 to −195) respond to different cellular activation in EL4 cells. The AP-1 site mediated the response to PMA stimulation while the κB site responded to IL-1 stimulation. These data suggest that the regulation of IL-2 gene expression is a complex process and multiple cis-acting regulatory sites interact to exert different effects in T cells representative of alternative stages of differentiation.