Abstract
ContextCortisol is released in ultradian pulses. The biological relevance of the resulting fluctuating cortisol concentration has not been explored.ObjectiveDetermination of the biological consequences of ultradian cortisol pulsatility.DesignA novel flow through cell culture system was developed to deliver ultradian pulsed or continuous cortisol to cells. The effects of cortisol dynamics on cell proliferation and survival, and on gene expression were determined. In addition, effects on glucocorticoid receptor (GR) expression levels and phosphorylation, as a potential mediator, were measured.ResultsPulsatile cortisol caused a significant reduction in cell survival compared to continuous exposure of the same cumulative dose, due to increased apoptosis. Comprehensive analysis of the transcriptome response by microarray identified genes with a differential response to pulsatile versus continuous glucocorticoid delivery. These were confirmed with qRT-PCR. Several transcription factor binding sites were enriched in these differentially regulated target genes, including CCAAT-displacement protein (CDP). A CDP regulated reporter gene (MMTV-luc) was, as predicted, also differentially regulated by pulsatile compared to continuous cortisol delivery. Importantly there was no effect of cortisol delivery kinetics on either GR expression, or activation (GR phosphoSer211).ConclusionsCortisol oscillations exert important effects on target cell gene expression, and phenotype. This is not due to differences in cumulative cortisol exposure, or either expression, or activation of the GR. This suggests a novel means to regulate GR function.
Highlights
Glucocorticoids undergo a circadian oscillation, with cortisol levels in humans peaking in the early morning and subsequently decreasing to low levels in the evening [1,2,3,4,5]
A CCAAT-displacement protein (CDP) regulated reporter gene (MMTV-luc) was, as predicted, differentially regulated by pulsatile compared to continuous cortisol delivery
There was no effect of cortisol delivery kinetics on either glucocorticoid receptor (GR) expression, or activation (GR phosphoSer211)
Summary
Glucocorticoids undergo a circadian oscillation, with cortisol levels in humans peaking in the early morning and subsequently decreasing to low levels in the evening [1,2,3,4,5] These diurnal fluctuations arise from signaling between the hypothalamic suprachiasmatic nucleus and the adrenal gland, and consist of both the autonomic nervous system and hormonal regulation of the HPA axis [6,7]. Ultradian rhythms of cortisol exist in healthy human volunteers, with a pulse of production every 1–2 hours [8,9] These secretory episodes occur with a constant frequency, but a variable amplitude, allowing for the production of the subsequent circadian rhythm [10,11,12,13,14,15,16]. The intrinsic temporal dynamics of this system exist with constant ligand exposure, but the impact of temporal fluctuations in ligand availability, likely the situation seen in-vivo, is unknown [11,28]
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