Pyrexia's effect on the CBG-cortisol thermocouple, rather than CBG cleavage, elevates the acute free cortisol response to TNF-α in humans.
Corticosteroid-binding globulin (CBG) cleavage promotes local cortisol delivery in inflammation. Enzymatic cleavage of high-affinity CBG to low-affinity CBG (haCBG to laCBG) occurs at inflammatory sites and is now measurable in vivo; however, the time kinetics of haCBG depletion following an inflammatory stimulus is unknown. Hence our aim was to determine the immediate effect of the key pro-inflammatory cytokine TNF-α on CBG levels and cleavage. We performed a crossover study of 12 healthy males receiving a TNF-α versus saline infusion, measuring total CBG, haCBG, laCBG and free and total cortisol hourly for 6 h. There was no change in total CBG or haCBG levels in the first 6 h of inflammation between the groups, suggesting that CBG cleavage is not activated nor is hepatic CBG production affected by TNF-α in this time frame. There was an early increase in the ratio of free:total cortisol, in association with pyrexia. This accords with data indicating that CBG acts a thermocouple in vivo, increasing free cortisol levels independent of elastase-driven cleavage.
a Endocrine and Metabolic Unit , Royal Adelaide Hospital , Adelaide , Australia.|b Discipline of Medicine , University of Adelaide , Adelaide , Australia.
Marni Anne
MA
Nenke
c The Centre of Inflammation and Metabolism and the Centre for Physical Activity Research, Rigshospitalet, University of Copenhagen, Copenhagen , Denmark.
Signe Tellerup
ST
Nielsen
c The Centre of Inflammation and Metabolism and the Centre for Physical Activity Research, Rigshospitalet, University of Copenhagen, Copenhagen , Denmark.
Louise Lang
LL
Lehrskov
d Steroid and Immunobiochemistry Laboratory, Canterbury Health Laboratories , Christchurch , New Zealand.
John Goodwyn
JG
Lewis
a Endocrine and Metabolic Unit , Royal Adelaide Hospital , Adelaide , Australia.|b Discipline of Medicine , University of Adelaide , Adelaide , Australia.|e SA Pathology , Chemical Pathology Directorate , Adelaide , Australia.
Wayne
W
Rankin
c The Centre of Inflammation and Metabolism and the Centre for Physical Activity Research, Rigshospitalet, University of Copenhagen, Copenhagen , Denmark.|f Department of Neuroanaesthesia, Righospitalet, Faculty of Health Sciences , University of Copenhagen , Copenhagen , Denmark.
Kirsten
K
Møller
a Endocrine and Metabolic Unit , Royal Adelaide Hospital , Adelaide , Australia.|b Discipline of Medicine , University of Adelaide , Adelaide , Australia.
David James
DJ
Torpy
D000328:Adult; D018592:Cross-Over Studies; D005334:Fever / Q000378:metabolism*; D006801:Humans; D006854:Hydrocortisone / Q000097:blood*; D007249:Inflammation / Q000097:blood*; D008297:Male; D014156:Transcortin / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*; D055815:Young Adult
D014409:Tumor Necrosis Factor-alpha; D014156:Transcortin; D006854:Hydrocortisone
Hypothalamic–pituitary–adrenal axis; cortisol; high-affinity CBG; inflammation; serpin; tumour necrosis factor-α