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

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 alpha and GR beta. We previously demonstrated that GR beta could antagonize GR alpha-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 alpha expression vector. Transfection of a GR beta expression vector alone did not result in IL-2 promoter repression in response to glucocorticoids. Furthermore, GR beta did not antagonize the repressive effects of GR alpha on IL-2 promoter activity. Surprisingly: overexpression of GR beta in Jurkat cells did not cause significant inhibition of GR alpha-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 alpha. GR beta can neither antagonize GR alpha-mediated transactivation nor transrepression in Jurkat cells, indicating a cell type-specific pattern of GR beta-mediated antiglucocorticoid activity. (C) 1997 Elsevier Science Ireland Ltd.