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- on CBG levels and cleavage. We performed a crossover study of 12 healthy males receiving a TNF- versus saline infusion, measuring total CBG, haCBG, laCBG and free and total cortisol hourly for 6h. There was no change in total CBG or haCBG levels in the first 6h of inflammation between the groups, suggesting that CBG cleavage is not activated nor is hepatic CBG production affected by TNF- 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.