title: Tissue mRNA expression of the glucocorticoid receptor and its splice variants in fatal critical illness.
abstract: BACKGROUND
  Critical illness results in activation of the hypothalamic-pituitary-adrenal (HPA) axis, which might be accompanied by a peripheral adaptation in glucocorticoid sensitivity. Tissue sensitivity is determined by the active glucocorticoid receptor GRalpha, of which two splice variants involving the hormone-binding domain exist, GRbeta and GR-P.
  
  
  OBJECTIVE
  To study tissue mRNA expression of the GR and its splice variants in fatal critical illness.
  
  
  METHODS
  We assessed mRNA expression of the GRalpha, GRbeta and GR-P variants in liver (n = 58) and muscle (n = 65) of patients who had died after intensive care, and had been randomized for insulin treatment. We analysed whether GR mRNA expression was associated with insulin treatment, cortisol levels and glucocorticoid treatment.
  
  
  RESULTS
  GRalpha and GR-P mRNA constituted 87 +/- 8% and 13 +/- 2%, respectively, of total GR mRNA in liver. GRbeta mRNA could only be amplified in five liver samples. All variants were present in most muscle samples (alpha = 96 +/- 11%, P = 3.9 +/- 0.4%, beta = 0.010 +/- 0.002%). GR expression was not associated with insulin therapy. A strong positive relationship was observed between the different GR variants in both liver and muscle (P < 0.001 for all). Serum cortisol levels were negatively associated with liver GRalpha and muscle GR-P expression (P < 0.05). mRNA expression of both liver GRalpha and GR-P, but not muscle GR, was substantially lower in patients who had received exogenous glucocorticoids (P < 0.01).
  
  
  CONCLUSIONS
  We demonstrate the presence of GRalpha and GR-P mRNA in liver and of GRalpha, GRbeta and GR-P mRNA in muscle, with no evidence for altered splicing in critical illness. In contrast to muscle GR, liver GR expression was substantially lower in patients receiving exogenous glucocorticoids.
authors.affiliation: Department of Internal Medicine, Section of Endocrinology, Erasmus MC, University Medical Centre, Rotterdam, the Netherlands.
authors.forename: R P
authors.initials: RP
authors.lastname: Peeters
authors.forename: A
authors.initials: A
authors.lastname: Hagendorf
authors.forename: I
authors.initials: I
authors.lastname: Vanhorebeek
authors.forename: T J
authors.initials: TJ
authors.lastname: Visser
authors.forename: W
authors.initials: W
authors.lastname: Klootwijk
authors.forename: D
authors.initials: D
authors.lastname: Mesotten
authors.forename: P J
authors.initials: PJ
authors.lastname: Wouters
authors.forename: J W
authors.initials: JW
authors.lastname: Koper
authors.forename: F H
authors.initials: FH
authors.lastname: de Jong
authors.forename: R A
authors.initials: RA
authors.lastname: Feelders
authors.forename: S W J
authors.initials: SW
authors.lastname: Lamberts
authors.forename: G
authors.initials: G
authors.lastname: Van den Berghe
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D017398:Alternative Splicing; D016638:Critical Illness / Q000628:therapy*; D005260:Female; D015870:Gene Expression; D005938:Glucocorticoids / Q000627:therapeutic use; D006801:Humans; D007328:Insulin / Q000627:therapeutic use; D007362:Intensive Care Units; D008099:Liver / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D009132:Muscles / Q000378:metabolism*; D011965:Receptors, Glucocorticoid / Q000235:genetics* / Q000378:metabolism
chemical_list: D005938:Glucocorticoids; D007328:Insulin; D011965:Receptors, Glucocorticoid