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

Identifieur interne : 000D51 ( Main/Exploration ); précédent : 000D50; suivant : 000D52

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

Auteurs : Christoph M. Bamberger [Allemagne] ; Tobias Else [Allemagne] ; Ana-Maria Bamberger [Allemagne] ; Frank Ulrich Beil [Allemagne] ; Heinrich M. Schulte [Allemagne]

Source :

RBID : ISTEX:F680D92384574046FAC10D72F82610324C0C19B5

Mots-clés :

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 GRα and GRβ. We previously demonstrated that GRβ could antagonize GRα-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 GRα expression vector. Transfection of a GRβ expression vector alone did not result in IL-2 promoter repression in response to glucocorticoids. Furthermore, GRβ did not antagonize the repressive effects of GRα on IL-2 promoter activity. Surprisingly, overexpression of GRβ in Jurkat cells did not cause significant inhibition of GRα-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 GRα. GRβ can neither antagonize GRα-mediated transactivation nor transrepression in Jurkat cells, indicating a cell type-specific pattern of GRβ-mediated antiglucocorticoid activity.


Url:
DOI: 10.1016/S0303-7207(97)00209-8


Affiliations:


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<div type="abstract" xml:lang="en">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 GRα and GRβ. We previously demonstrated that GRβ could antagonize GRα-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 GRα expression vector. Transfection of a GRβ expression vector alone did not result in IL-2 promoter repression in response to glucocorticoids. Furthermore, GRβ did not antagonize the repressive effects of GRα on IL-2 promoter activity. Surprisingly, overexpression of GRβ in Jurkat cells did not cause significant inhibition of GRα-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 GRα. GRβ can neither antagonize GRα-mediated transactivation nor transrepression in Jurkat cells, indicating a cell type-specific pattern of GRβ-mediated antiglucocorticoid activity.</div>
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