Corticosteroid resistance in sepsis is influenced by microRNA-124–induced downregulation of glucocorticoid receptor-α*
Antiglucocorticoid
DOI:
10.1097/ccm.0b013e31825b8ebc
Publication Date:
2012-07-31T07:10:54Z
AUTHORS (8)
ABSTRACT
Acquired glucocorticoid resistance frequently complicates the therapy of sepsis. It leads to an exaggerated proinflammatory response and has been related altered expression profiles receptor isoforms receptor-α (mediating anti-inflammatory effects) receptor-β (acting as a dominant negative inhibitor). We investigated impact on effects in human T-cells. hypothesized that 1) changes ratio 2) is controlled by microRNA-mediated gene silencing.Laboratory-based study.University research laboratory.Healthy volunteers, sepsis patients.First, T-cells from healthy volunteers (native CD3/CD28-stimulated cells with or without addition hydrocortisone) were analyzed for receptor-isoforms quantitative polymerase chain reaction. Additionally, silencing siRNA transfection determined. Secondly, was evaluated cloning receptor-α-specific 3'-untranslated-region reporter construct subsequent experiments cell cultures. Effects miRNA Jurkat (quantitative reaction Western blotting). Finally, receptor-α, receptor-β, miR-124 tested patients (n=24).Stimulation induced significant upregulation (not receptor-β) thereby possibly rendering more sensitive glucocorticoids; this T-cell hindered hydrocortisone. Silencing doubled inhibitory glucocorticoids interleukin-2 production. MicroRNA-124 proved specifically downregulate receptor-α. Furthermore, glucocorticoid-induced three-fold microRNA-124 found. exhibited slightly decreased increased levels, whereas two-fold upregulated (p<.01) remarkable interindividual variability.Glucocorticoid treatment induces miR-124, which downregulates limiting glucocorticoids. Steroid might aggravate high levels.
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