Cell-specific expression and signaling of glucocorticoid receptor isoforms over time in critically ill patients with a low inflammatory response.
| Title: | Cell-specific expression and signaling of glucocorticoid receptor isoforms over time in critically ill patients with a low inflammatory response. |
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| Authors: | Poupouzas G; 1st Department of Critical Care Medicine, Evangelismos Hospital, School of Medicine, National & Kapodistrian University of Athens, Athens, Greece.; Lotsios NS; 1st Department of Critical Care Medicine, Evangelismos Hospital, School of Medicine, National & Kapodistrian University of Athens, Athens, Greece.; Vrettou CS; 1st Department of Critical Care Medicine, Evangelismos Hospital, School of Medicine, National & Kapodistrian University of Athens, Athens, Greece.; Issaris V; 1st Department of Critical Care Medicine, Evangelismos Hospital, School of Medicine, National & Kapodistrian University of Athens, Athens, Greece.; Keskinidou C; 1st Department of Critical Care Medicine, Evangelismos Hospital, School of Medicine, National & Kapodistrian University of Athens, Athens, Greece.; Papavassiliou KA; 1st University Department of Respiratory Medicine, 'Sotiria' Chest Hospital, School of Medicine, National and Kapodistrian University of Athens, Athens, 11527, Greece.; Halioti A; 1st Department of Critical Care Medicine, Evangelismos Hospital, School of Medicine, National & Kapodistrian University of Athens, Athens, Greece.; Botoula E; Department of Endocrinology, Diabetes and Metabolism, National Expertise Center for Rare Endocrine Diseases, Evangelismos Hospital, Athens, Greece.; Tzanela M; Department of Endocrinology, Diabetes and Metabolism, National Expertise Center for Rare Endocrine Diseases, Evangelismos Hospital, Athens, Greece.; Papavassiliou AG; Department of Biological Chemistry, School of Medicine, National and Kapodistrian University of Athens, Athens, 11527, Greece.; Kotanidou A; 1st Department of Critical Care Medicine, Evangelismos Hospital, School of Medicine, National & Kapodistrian University of Athens, Athens, Greece.; Vassiliadi DA; Department of Endocrinology, Diabetes and Metabolism, National Expertise Center for Rare Endocrine Diseases, Evangelismos Hospital, Athens, Greece.; Vassiliou AG; 1st Department of Critical Care Medicine, Evangelismos Hospital, School of Medicine, National & Kapodistrian University of Athens, Athens, Greece. alvass75@gmail.com.; Dimopoulou I; 1st Department of Critical Care Medicine, Evangelismos Hospital, School of Medicine, National & Kapodistrian University of Athens, Athens, Greece. idimo@otenet.gr. |
| Source: | Critical care (London, England) [Crit Care] 2025 Aug 29; Vol. 29 (1), pp. 390. Date of Electronic Publication: 2025 Aug 29. |
| Publication Type: | Journal Article; Observational Study |
| Language: | English |
| Journal Info: | Publisher: BioMed Central Ltd Country of Publication: England NLM ID: 9801902 Publication Model: Electronic Cited Medium: Internet ISSN: 1466-609X (Electronic) Linking ISSN: 13648535 NLM ISO Abbreviation: Crit Care Subsets: MEDLINE |
| Imprint Name(s): | Publication: London, UK : BioMed Central Ltd; Original Publication: London : Current Science Ltd, c1997- |
| MeSH Terms: | Receptors, Glucocorticoid*/analysis ; Receptors, Glucocorticoid*/blood ; Critical Illness*; Adrenocorticotropic Hormone/blood ; Adrenocorticotropic Hormone/analysis ; Cytokines/analysis ; Cytokines/blood ; Dual Specificity Phosphatase 1/analysis ; Dual Specificity Phosphatase 1/blood ; Hydrocortisone/blood ; Hydrocortisone/analysis ; Inflammation/blood ; Inflammation/physiopathology ; Intensive Care Units/organization & administration ; Intensive Care Units/statistics & numerical data ; Interleukin-6/blood ; Interleukin-6/analysis ; Protein Isoforms/blood ; Protein Isoforms/analysis ; Signal Transduction/physiology ; Adult ; Aged ; Female ; Humans ; Male ; Middle Aged ; Prospective Studies ; Case-Control Studies |
| Abstract: | 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.; (© 2025. The Author(s).) |
| Competing Interests: | Declarations. Ethics approval and consent to participate: The research ethics committee of “Evangelismos” Hospital approved the study (444–28/09/2023). Informed written consent was obtained from all patients’ legal surrogates prior to inclusion. Consent for publication: Not applicable. Competing interests: The authors declare no competing interests. |
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| Contributed Indexing: | Keywords: DUSP1; GC sensitivity; GCR isoforms; GILZ; Immune cells |
| Substance Nomenclature: | 9002-60-2 (Adrenocorticotropic Hormone); 0 (Cytokines); EC 3.1.3.48 (Dual Specificity Phosphatase 1); WI4X0X7BPJ (Hydrocortisone); 0 (Interleukin-6); 0 (Protein Isoforms); 0 (Receptors, Glucocorticoid) |
| Entry Date(s): | Date Created: 20250829 Date Completed: 20250830 Latest Revision: 20250902 |
| Update Code: | 20260130 |
| PubMed Central ID: | PMC12398082 |
| DOI: | 10.1186/s13054-025-05628-9 |
| PMID: | 40883751 |
| Database: | MEDLINE |
Journal Article; Observational Study