HSP90α and HSP72 work together as the only two essential components of the five-protein system for allowing hGRα to bind the incoming steroid hormone by enhancing its affinity for the ligand. HSP90 regulates ligand binding, as well as cytoplasmic retention of hGRα by exposing the ligand-binding site and masking the two nuclear localization sequences. In the absence of ligand, the hGRα resides mostly in the cytoplasm of cells as part of a hetero-oligomeric complex, which contains chaperone heat shock proteins (HSPs) 90 and 70. The hGRβ does not bind glucocorticoid agonists and exerts a dominant negative effect on the transcriptional activity of hGRα. The residing in the cytoplasm hGRα functions as a ligand-dependent transcription factor. Alternative splicing of exon nine generates two highly homologous receptor isoforms, hGRα, and hGRβ. The human glucocorticoid receptor (hGR) is encoded by the NR3C1 gene, which is located on the long arm of chromosome 5 (5q31.3) and is composed of ten exons. In humans, glucocorticoids (GCs) exert their effects through binding to their cognate receptor, the glucocorticoid receptor, a ligand-dependent transcription factor. Also, decreased activity of the cortisol metabolizing enzymes impairs cortisol clearance, enhances hypercortisolism, and suppresses ACTH secretion by feedback inhibition. The activation of the hypothalamic–pituitary–adrenal (HPA) axis results in increased cortisol concentrations driven by increased secretion of ACTH. Sepsis is a life-threatening organ dysfunction caused by a dysregulated host response to infection. At this stage, hGR is able to predict sepsis and outcome and is related to stress-activated bio-molecules and organ dysfunction. ConclusionsĪcute-phase sepsis is associated with increased hGR expression and cortisol concentrations, possibly implying no need for exogenous steroids. HGR protein was higher in S compared to H and SIRS hGRα mRNA was higher in S compared to H ( p 0.85, p 0.95, p < 0.04). ELISA was used to evaluate serum ILs and extracellular (e) HSPs (eHSP72, eHSP90α). Serum prolactin, ACTH, and cortisol concentrations were also measured. Intracellular hGR and HSP expression in monocytes and/or neutrophils was evaluated using four-colour flow cytometry. Total mRNA was isolated from peripheral blood samples and cDNA was prepared. Patients consecutively admitted to a university hospital intensive care unit (ICU) with S ( n = 48) or SIRS ( n = 40) were enrolled in the study. 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.
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