Glucocorticoids entrain molecular clock components in human peripheral cells

Abstract

In humans, shift work induces a desynchronization between the circadian system and the outside world, which contributes to shift work-associated medical disorders. Using a simulated night shift experiment, we previously showed that 3 d of bright light at night fully synchronize the central clock to the inverted sleep schedule, whereas the peripheral clocks located in peripheral blood mononuclear cells (PBMCs) took longer to reset. This underlines the need for testing the effects of synchronizers on both the central and peripheral clocks. Glucocorticoids display circadian rhythms controlled by the central clock and are thought to act as synchronizers of rodent peripheral clocks. In the present study, we tested whether the human central and peripheral clocks were sensitive to exogenous glucocorticoids (Cortef) administered in the late afternoon. We showed that 20 mg Cortef taken orally acutely increased PER1 expression in PBMC peripheral clocks. After 6 d of Cortef administration, the phases of central markers were not affected, whereas those of PER2-3 and BMAL1 expression in PBMCs were shifted by ∼ 9.5-11.5 h. These results demonstrate, for the first time, that human peripheral clocks are entrained by glucocorticoids. Importantly, they suggest innovative interventions for shift workers and jet-lag travelers, combining synchronizing agents for the central and peripheral clocks.

Simulated Night Shift Disrupts Circadian Rhythms of Immune Functions in Humans

“…We set the period parameter of the regression to 24 h, facilitating the assessment of phase shifts between and within subjects. A rhythm was considered significant when the 95% confidence interval of the calculated 24-h and/or 12-h amplitude did not include the zero value, as confirmed by p values given by the nlmixed procedure (Tables I-III, Supplemental Table I) (35).…”

“…Harmonic regressions were applied to group data (nonlinear mixed-effect models using nlmixed SAS procedure; SAS Institute, Cary, NC) (35). We set the period parameter of the regression to 24 h, facilitating the assessment of phase shifts between and within subjects.…”

“…For plasma melatonin, time of fitted maximum (phase) and amplitude were assessed using a three-harmonic regression (35,47). We calculated the composite phase via a manual process using fitted amplitude and phase values from the three harmonics (6-, 12-, and 24-h periods), followed by a bootstrap strategy (1000 repetitions) to calculate the SEM (35,48).…”

“…We calculated the composite phase via a manual process using fitted amplitude and phase values from the three harmonics (6-, 12-, and 24-h periods), followed by a bootstrap strategy (1000 repetitions) to calculate the SEM (35,48). The amplitude was defined as the mean-to-trough difference of the first harmonic of the regression (49).…”

“…In central and peripheral clocks, rhythms with a period of ∼ 24 h are generated by autoregulatory feedback loops involving clock genes (e.g., CLOCK, BMAL1, Period or PER1-3, Cryptochrome or CRY1-2) (32). Hence, immune cells (e.g., monocytes/macrophages, lymphocytes) have the molecular clock machinery and display circadian gene expression (19,20,25,(33)(34)(35).…”