Endogenous glucocorticoid receptor signaling drives rhythmic changes in human T-cell subset numbers and the expression of the chemokine receptor CXCR4.
In humans, numbers of circulating naive T cells strongly decline in the morning, which was suggested to be mediated by cortisol, inducing a CXCR4 up-regulation with a subsequent extravasation of the cells. As a systematic evaluation of this assumption is lacking, we investigated in two human placebo-controlled studies the effects of the glucocorticoid receptor (GR) antagonist mifepristone (200 mg orally at 23:00) and of suppressing endogenous cortisol with metyrapone (1 g orally at 04:00) on temporal changes in CXCR4 expression and numbers of different T-cell subsets using flow cytometry. Mifepristone attenuated, and metyrapone completely blocked, the morning increase in CXCR4 expression on naive T cells. In parallel, both substances also hindered the decline in naive T-cell numbers with this effect, however, being less apparent after mifepristone. We identified, and confirmed in additional in vitro studies, a partial agonistic GR effect of mifepristone at night (i.e., between 02:00 and 03:30) that could explain the lower antagonistic efficacy of the substance on CXCR4 expression and naive T-cell counts. CXCR4 expression emerged to be a most sensitive marker of GR signaling. Our studies jointly show that endogenous cortisol, specifically via GR activation, causes the morning increase in CXCR4 expression and the subsequent extravasation of naive T cells, thus revealing an important immunological function of the morning cortisol rise.
1Department of Neuroendocrinology, University of Lübeck, Ratzeburger Allee 160, Lübeck 23538, Germany. lange@uni-luebeck.de.
Luciana
L
Besedovsky
Jan
J
Born
Tanja
T
Lange
D000328:Adult; D054377:Chemokine CXCL12 / Q000378:metabolism; D002940:Circadian Rhythm / Q000187:drug effects; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D006854:Hydrocortisone / Q000378:metabolism; D008297:Male; D008797:Metyrapone / Q000494:pharmacology; D015735:Mifepristone / Q000494:pharmacology; D019718:Receptors, CXCR4 / Q000378:metabolism; D011965:Receptors, Glucocorticoid / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D016176:T-Lymphocyte Subsets / Q000187:drug effects / Q000378:metabolism*; D055815:Young Adult
D054377:Chemokine CXCL12; D019718:Receptors, CXCR4; D011965:Receptors, Glucocorticoid; D015735:Mifepristone; D006854:Hydrocortisone; D008797:Metyrapone
CXCL12; circadian rhythm; cortisol