title: Increased glucocorticoid receptor expression in sepsis is related to heat shock proteins, cytokines, and cortisol and is associated with increased mortality.
abstract: BACKGROUND
  The purposes of this study are to examine if the human glucocorticoid receptor (hGR) isoform-α mRNA and hGR protein expressions are deficient in the acute phase of sepsis (S) compared to systemic inflammatory response syndrome (SIRS) and healthy subjects (H) and to evaluate if the hGRα and hGR alterations are associated with cortisol changes and if they are related to (1) extracellular and intracellular heat shock proteins (HSP) 72 and 90α; (2) ACTH, prolactin, and interleukins (ILs); and (3) outcome.
  
  
  METHODS
  Patients consecutively admitted to a university hospital intensive care unit (ICU) with S (n = 48) or SIRS (n = 40) were enrolled in the study. Thirty-five H were also included. Total mRNA was isolated from peripheral blood samples and cDNA was prepared. RT-PCR was performed. Intracellular hGR and HSP expression in monocytes and/or neutrophils was evaluated using four-colour flow cytometry. Serum prolactin, ACTH, and cortisol concentrations were also measured. ELISA was used to evaluate serum ILs and extracellular (e) HSPs (eHSP72, eHSP90α).
  
  
  RESULTS
  hGR protein was higher in S compared to H and SIRS; hGRα mRNA was higher in S compared to H (p < 0.05). In sepsis, hGR protein and eHSP72 were higher among non-survivors compared to survivors (p < 0.05). The hGR MFI and hGRα mRNA fold changes were significantly related to each other (rs= 0.64, p < 0.001). Monocyte hGR protein expression was positively correlated with extracellular and intracellular HSPs, cortisol, and ILs and negatively to organ dysfunction (p < 0.05). HSPs, hGR, and cortisol were able to discriminate sepsis from SIRS (AUROC > 0.85, p < 0.05). In sepsis, monocyte-hGR protein and eHSP72 were strong predictors of mortality (AUROC > 0.95, p < 0.04).
  
  
  CONCLUSIONS
  Acute-phase sepsis is associated with increased hGR expression and cortisol concentrations, possibly implying no need for exogenous steroids. At this stage, hGR is able to predict sepsis and outcome and is related to stress-activated bio-molecules and organ dysfunction.
authors.affiliation: First Critical Care Department, National and Kapodistrian University of Athens, Athens, Greece.|Pediatric Intensive Care Unit, University Hospital, University of Crete, 71500, Heraklion, Crete, Greece.
authors.forename: Konstantinos
authors.initials: K
authors.lastname: Vardas
authors.affiliation: Pediatric Intensive Care Unit, University Hospital, University of Crete, 71500, Heraklion, Crete, Greece.
authors.forename: Stavroula
authors.initials: S
authors.lastname: Ilia
authors.affiliation: Division of Endocrinology, Metabolism and Diabetes, First Department of Pediatrics, 'Aghia Sophia' Children's Hospital and Division of Endocrinology and Metabolism, Biomedical Research Foundation of the Academy of Athens, National and Kapodistrian University of Athens, Athens, Greece.
authors.forename: Amalia
authors.initials: A
authors.lastname: Sertedaki
authors.affiliation: Division of Endocrinology, Metabolism and Diabetes, First Department of Pediatrics, 'Aghia Sophia' Children's Hospital and Division of Endocrinology and Metabolism, Biomedical Research Foundation of the Academy of Athens, National and Kapodistrian University of Athens, Athens, Greece.
authors.forename: Evangelia
authors.initials: E
authors.lastname: Charmandari
authors.affiliation: First Department of Internal Medicine-Propaedeutic, National and Kapodistrian University of Athens, Athens, Greece.
authors.forename: Efrossini
authors.initials: E
authors.lastname: Briassouli
authors.affiliation: First Department of Internal Medicine-Propaedeutic, National and Kapodistrian University of Athens, Athens, Greece.
authors.forename: Dimitris
authors.initials: D
authors.lastname: Goukos
authors.affiliation: First Critical Care Department, National and Kapodistrian University of Athens, Athens, Greece.
authors.forename: Kleovoulos
authors.initials: K
authors.lastname: Apostolou
authors.affiliation: Immunology-Histocompatibility Department, Evangelismos Hospital, Athens, Greece.
authors.forename: Katerina
authors.initials: K
authors.lastname: Psarra
authors.affiliation: Department of Endocrinology-Diabetes, Evangelismos Hospital, Athens, Greece.
authors.forename: Efthimia
authors.initials: E
authors.lastname: Botoula
authors.affiliation: Department of Endocrinology-Diabetes, Evangelismos Hospital, Athens, Greece.
authors.forename: Stylianos
authors.initials: S
authors.lastname: Tsagarakis
authors.affiliation: First Critical Care Department, National and Kapodistrian University of Athens, Athens, Greece.
authors.forename: Eleni
authors.initials: E
authors.lastname: Magira
authors.affiliation: First Critical Care Department, National and Kapodistrian University of Athens, Athens, Greece.
authors.forename: Christina
authors.initials: C
authors.lastname: Routsi
authors.affiliation: Section on Endocrinology and Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health, Bethesda, MD, 20892, USA.
authors.forename: Constantine A
authors.initials: CA
authors.lastname: Stratakis
authors.affiliation: First Critical Care Department, National and Kapodistrian University of Athens, Athens, Greece.
authors.forename: Serafim
authors.initials: S
authors.lastname: Nanas
authors.affiliation: Pediatric Intensive Care Unit, University Hospital, University of Crete, 71500, Heraklion, Crete, Greece. ggbriass@otenet.gr.
authors.forename: George
authors.identifier: http://orcid.org/0000-0003-0928-6183
authors.initials: G
authors.lastname: Briassoulis
keywords: Cortisol; Glucocorticoid receptor (GR); HSP90α; Heat shock protein 72; SIRS; Sepsis