The regulation of the expression of human interleukin-2 gene.

Abstract

Interleukin-2 (IL-2) is a glycoprotein produced by CD4$\sp{+}$ T lymphocytes after mitogenic or antigenic stimulation. IL-2 is required for the proliferation, differentiation and function of both T and B cells, and the IL-2 gene expression is restricted to activated T cells. This work investigates the functions of the cis-acting regulatory sites within the IL-2 enhancer region and the mechanism(s) that control the cell-specific expression of the IL-2 gene. Our results indicate that the IL-2 gene expression is regulated by the cell-specific derepression of its promoter and the positive and negative regulatory effects of the cis-acting sites in the enhancer. The functions of the IL-2 gene regulatory sites have been analyzed in the native IL-2 enhancer and promoter sequences by investigating the transient expression of site-specific mutants of an IL2-CAT plasmid in human or mouse T cells. Different functions have been observed for these regulatory sites in T cells. The NFAT, the distal octamer and the proximal octamer sites have a silencing effect on IL-2 transcription in resting cells, and act as enhancers in the presence of stimulation; the distal and proximal purine box sites display disparate effects on IL-2 gene expression in different T cells; the $\kappa$B and the AP-1 sites respond to IL-1 or PMA stimulation, respectively. The mechanism(s) of the restricted and inducible IL-2 gene expression have been investigated by analyzing the transactivation of the IL-2 gene by the infected cell protein 0 (ICP0) of the herpes simplex virus type 1. We have found that the IL-2 gene expression is controlled in part by the derepression of its promoter between the $-$51 to +18 region in a cell-specific fashion. This derepression requires both an intact TATA box sequence and the transcription initiation site of IL-2 and is sensitive to an immunosuppressant, cyclosporin A. In electrophoretic mobility shift assays, protein complexes have been found to bind to this IL-2 promoter region and correlate with the cell-specific depression effect(s). No cyclosporin A effect has been observed on these DNA-protein complexes. These observations suggest that the IL-2 promoter is regulated in part by derepression, and the lineage specific gene expression can be regulated by factors that regulate the derepression in a cell-specific fashion.