title: How changes in affinity of corticosteroid-binding globulin modulate free cortisol concentration.
abstract: BACKGROUND
  Recent studies of corticosteroid-binding globulin (CBG) indicate that it does not merely transport cortisol passively but also actively regulates its release in the circulation. We show how CBG binding affinity can vary to give changes in free cortisol concentration in a physiologically relevant range.
  
  
  OBJECTIVE
  The objective was to determine how the binding affinity of plasma CBG is affected by glycosylation, changes in body temperature, and the conformational change induced by proteases at sites of inflammation.
  
  
  METHODS
  Binding assays were performed over a range of temperatures with plasma and recombinant CBG to determine the contribution of glycosylation. The role of conformational change was assessed by measuring binding affinities of plasma CBG before and after reactive loop cleavage by neutrophil elastase.
  
  
  METHODS
  Determination of binding constants allows calculation of clinically relevant changes in CBG saturation and free cortisol concentrations.
  
  
  RESULTS
  On reactive loop cleavage at inflammation sites, CBG can continue to act as a buffered source of cortisol, although with a much reduced affinity, to give a potential quadrupling of free cortisol. Predicted increases in systemic free cortisol resulting from elevated body temperatures, previously reported based on affinity measurements using nonglycosylated recombinant CBG, were shown here to be considerably increased using glycosylated plasma CBG, with a doubling for every 2°C rise in body temperature.
  
  
  CONCLUSIONS
  The ability of CBG to modulate free cortisol levels in blood must be considered in the understanding and management of disease processes, as illustrated here with predictable changes in inflammation and fever.
authors.affiliation: Department of Hematology, University of Cambridge, Cambridge Institute for Medical Research, Cambridge CB2 0XY, United Kingdom.
authors.forename: Wee Lee
authors.initials: WL
authors.lastname: Chan
authors.forename: Robin W
authors.initials: RW
authors.lastname: Carrell
authors.forename: Aiwu
authors.initials: A
authors.lastname: Zhou
authors.forename: Randy J
authors.initials: RJ
authors.lastname: Read
mesh_terms: D006031:Glycosylation; D006801:Humans; D006854:Hydrocortisone / Q000097:blood* / Q000378:metabolism; D011485:Protein Binding; D013237:Stereoisomerism; D013696:Temperature; D014156:Transcortin / Q000378:metabolism*
chemical_list: D014156:Transcortin; D006854:Hydrocortisone