Increased glucocorticoid receptor expression in sepsis is related to heat shock proteins, cytokines, and cortisol and is associated with increased mortality

Abstract

BackgroundThe 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.MethodsPatients 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).ResultshGR 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 (r s = 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).ConclusionsAcute-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.

Decreased glucocorticoid receptor expression during critical illness

“…On the contrary, GCR hormone‐binding activity was studied in septic patients and it was shown that the GCR count and affinity in septic patients did not differ from those in normal controls, suggesting that glucocorticoids could still be effective in the hemodynamic compensatory phase of sepsis . A very recent study also showed increased glucocorticoid receptor alpha expression in the acute phase of sepsis . In critical illness, only one study has demonstrated down‐regulation of cortisol binding in ventilated patients …”

“…44 A very recent study also showed increased glucocorticoid receptor alpha expression in the acute phase of sepsis. 45 In critical illness, only one study has demonstrated down-regulation of cortisol binding in ventilated patients. 46 The description of a dominant negative effect of the GCR-β isotype has focused the interest of many researchers on this protein as a potential mechanism of GCR resistance.…”

Glucocorticoid receptor activation is associated with increased resistance to heat‐induced hyperthermia and injury

“…On the other hand, released GR is known to transcriptionally upregulate anti‐inflammatory cytokines and suppress pro‐inflammatory cytokines. It has been shown that both GR and HSPs are significantly elevated in the leucocytes of patients with severe sepsis …”

Critical illness-related corticosteroid insufficiency (CIRCI): a narrative review from a Multispecialty Task Force of the Society of Critical Care Medicine (SCCM) and the European Society of Intensive Care Medicine (ESICM)

“…These changes are considered maladaptive, since GR-α upregulation was shown to augment the effects of available glucocorticoids [81]. Clinical studies in patients with septic shock [79,80] and ARDS [7] have provided evidence of an association between the degree of intracellular glucocorticoid resistance, disease severity, and mortality.…”

“…Tissue resistance to glucocorticoids has been implicated in chronic inflammatory diseases such as chronic obstructive pulmonary disease, severe asthma, systemic lupus erythematosus, ulcerative colitis, and rheumatoid arthritis [76]. Glucocorticoid resistance is also recognized as a potential complication of critical illness, with most of the evidence originating from the sepsis and ARDS clinical and experimental literature [75][76][77][78][79][80][81]. Critical illness is associated with reduced GR-α density and transcription [7,25,82,83] and increased GR-β (dominant negative activity on GR-induced transcription) [80,83,84].…”