Cell-specific expression and signaling of glucocorticoid receptor isoforms over time in critically ill patients with a low inflammatory response

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BACKGROUND: Glucocorticoid (GC) signaling plays a crucial role in immune regulation during critical illness, but cell-specific responses remain poorly understood. While previous studies have predominantly examined glucocorticoid receptor (GCR)-α and GCR-β, the roles of alternative isoforms (GCR-γ, GCR-P) and the downstream effectors GC-induced leucine zipper (GILZ) and dual-specific phosphatase 1 (DUSP1) across different immune cell populations in critical illness remain unexplored. METHODS: In this prospective, observational study, we enrolled 43 critically ill patients and 25 healthy controls. Longitudinal blood samples were collected at ICU admission (24-48 h) and days 4 (4d), 8 (8d), and 14 (14d). We quantified the mRNA expression of four GCR variants (GCR-α, GCR-β, GCR-γ, and GCR-P) and GC downstream targets (GILZ and DUSP1) in isolated polymorphonuclear cells (PMNs) and peripheral blood mononuclear cells (PBMCs) via RT‒PCR. Serum cortisol, adrenocorticotropic hormone (ACTH), and cytokines (interleukin (IL)-6 and IL-10) were measured concurrently. Statistical analyses included mixed-effects modeling to assess temporal and cell-specific patterns. RESULTS: PMNs exhibited sustained downregulation of GCR-α, GCR-β, and GCR-γ, with preserved GILZ expression, while GCR-P remained stable. In PBMCs, GCR-α, GCR-β, GCR-γ, and GILZ levels showed no significant changes compared to controls, yet GCR-P was upregulated. DUSP1 was downregulated in PMNs and elevated in PBMCs. Negative correlations emerged between IL-6 and both GILZ and DUSP1. All expression patterns remained stable across time points in the subset of patients who completed the 2-week study despite dynamic ACTH changes and persistently elevated cortisol. CONCLUSIONS: PMNs show reduced GCR-α/β/γ with preserved GILZ, while PBMCs maintain GCR-α/β/γ but upregulate GCR-P and DUSP1. These findings highlight divergent GC responsiveness between innate and adaptive immune cells, with implications for cortisol's role in immune regulation during critical illness and may reflect cell-specific effects driven by changes in glucocorticoid receptor signaling.

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