Selective glucocorticoid receptor translational isoforms reveal glucocorticoid-induced apoptotic transcriptomes

Area of Science:

• Molecular biology
• Immunology
• Cell biology

Background:

• Glucocorticoids (GCs) exert anti-inflammatory and antineoplastic effects partly through T-cell apoptosis.
• Glucocorticoid receptor (GR) translational isoforms possess distinct proapoptotic activities, as observed in osteosarcoma cells.

Purpose of the Study:

• To investigate whether GR isoforms selectively induce apoptosis in Jurkat T lymphoblastic leukemia cells.
• To identify genes and pathways involved in GR isoform-mediated apoptosis in T-cells.

Main Methods:

• Generation of Jurkat T-cell lines stably expressing individual GR isoforms.
• Treatment with dexamethasone (DEX) and assessment of apoptosis.
• cDNA microarray analysis to compare gene expression profiles.
• Chromatin immunoprecipitation assays to investigate GR isoform functions.

Main Results:

• Dexamethasone (DEX) induced apoptosis in Jurkat cells expressing GR-A, -B, or -C isoforms, but not GR-D.
• Distinct proapoptotic transcriptomes were identified in DEX-sensitive (GR-C3) versus insensitive (GR-D3) cells.
• Genes directly involved in apoptosis and cell killing were regulated by proapoptotic GR-C3 but not GR-D3.
• All GR isoforms suppressed mitogen-stimulated cytokines, while GR-C isoforms were upregulated in activated T cells.

Conclusions:

• GR isoforms exhibit selective proapoptotic functions in T-cells, mediated by distinct transcriptomes and chromatin modification abilities.
• The differential expression and function of GR isoforms contribute to the tissue- and individual-selective actions of glucocorticoids.
• These findings provide a basis for developing improved glucocorticoid therapeutics targeting specific GR isoforms.