Pyrexia's effect on the CBG-cortisol thermocouple, rather than CBG cleavage, elevates the acute free cortisol response to TNF-α in humans

TY - JOUR

T1 - Pyrexia's effect on the CBG-cortisol thermocouple, rather than CBG cleavage, elevates the acute free cortisol response to TNF-α in humans

AU - Nenke, Marni Anne

AU - Nielsen, Signe Tellerup

AU - Lehrskov, Louise Lang

AU - Lewis, John Goodwyn

AU - Rankin, Wayne

AU - Møller, Kirsten

AU - Torpy, David James

PY - 2017

Y1 - 2017

N2 - 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.

AB - 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.

KW - Adult

KW - Cross-Over Studies

KW - Fever/metabolism

KW - Humans

KW - Hydrocortisone/blood

KW - Inflammation/blood

KW - Male

KW - Transcortin/metabolism

KW - Tumor Necrosis Factor-alpha/pharmacology

KW - Young Adult

U2 - 10.1080/10253890.2017.1292420

DO - 10.1080/10253890.2017.1292420

M3 - Journal article

C2 - 28166688

SN - 1025-3890

VL - 20

SP - 183

EP - 188

JO - Stress: The International Journal on the Biology of Stress

JF - Stress: The International Journal on the Biology of Stress

IS - 2

ER -