Regulation of the human interleukin-2 gene by the α and β isoforms of the glucocorticoid receptor

Abstract

The immunosuppressive effects of glucocorticoids are largely due to transcriptional inhibition of immunologically relevant genes, such as the interleukin-2 (IL-2) gene. These effects are mediated by the intracellular glucocorticoid receptor (GR). In humans, alternative splicing of the GR precursor mRNA gives rise to two receptor isoforms, termed GR α and GR β. We previously demonstrated that GR β could antagonize GR α-mediated transactivation of a glucocorticoid-responsive element (GRE)-driven reporter gene in COS-7 cells. The present study was designed to analyze the roles of the two GR isoforms on glucocorticoid-mediated transrepression of the IL-2 gene. Using a recently developed transfection technique, we demonstrate that in primary human lymphocytes, stimulation of a 548 bp IL-2 promoter-luciferase reporter construct by phorbol ester and calcium ionophore is reversed by dexamethasone to a similar extent as in Jurkat T lymphoma cells transfected with a GR α expression vector. Transfection of a GR β expression vector alone did not result in IL-2 promoter repression in response to glucocorticoids. Furthermore, GR β did not antagonize the repressive effects of GR α on IL-2 promoter activity. Surprisingly, overexpression of GR β in Jurkat cells did not cause significant inhibition of GR α-induced transactivation of a GRE-dependent luciferase reporter gene either. We conclude that the transrepressive effect of glucocorticoids on IL-2 gene transcription is exclusively mediated by GR α. GR β can neither antagonize GR α-mediated transactivation nor transrepression in Jurkat cells, indicating a cell type-specific pattern of GR β-mediated antiglucocorticoid activity.