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Circadian Interleukin-6 Secretion and Quantity and Depth of Sleep

Sleep Research and Treatment Center (A.N.V., E.O.B., A.K.), Department of Psychiatry, Pennsylvania State University, Hershey, Pennsylvania 17033; Developmental Endocrinology Branch (D.A.P., A.L., K.Z., G.P.C.), National Institute of Child Health Development, National Institutes of Health, Bethesda, Maryland 20892; Clinical Neuroendocrinology Branch (P.P., M.-L.W., J.L., P.W.G.), National Institute for Mental Health, Bethesda, Maryland 20892; Bioengineering and Chronobiology Laboratories (R.C.H.), ETSI Telecommunications, Campus Universitario Vigo, Pontevedra 36200, Spain; and Endocrine Unit (G.M.), Evgenidion Hospital, Athens University, Athens 11528, Greece

Address all correspondence and requests for reprints to: Alexandros N. Vgontzas, M.D., Sleep Research and Treatment Center, Department of Psychiatry, Pennsylvania State University, College of Medicine, 500 University Drive, Hershey, Pennsylvania 17033. E-mail: axv3{at}psu.edu

	Abstract

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Patients with pathologically increased daytime sleepiness and fatigue have elevated levels of circulating interleukin-6 (IL-6). The latter is an inflammatory cytokine, which causes sickness manifestations, including somnolence and fatigue, and activation of the hypothalamic-pituitary-adrenal axis. In this study, we examined: 1) the relation between serial measurements of plasma IL-6 and quantity and depth of sleep, evaluated by polysomnography; and 2) the effects of sleep deprivation on the nyctohemeral pattern of IL-6 secretion. Eight healthy young male volunteers were sampled for 24 h twice, at the baseline state, after a normal night’s sleep and after total overnight sleep deprivation. At the baseline state, IL-6 was secreted in a biphasic circadian pattern with two nadirs at 0800 and 2100 and two zeniths at 1900 and 0500 (P < 0.01). The baseline amount of sleep correlated negatively with the overall daytime secretion of the cytokine (P < 0.05). Also, depth of sleep at baseline correlated negatively with the postdeprivation increase of daytime secretion of IL-6 (P < 0.05). Sleep deprivation changed the temporal pattern of circadian IL-6 secretion but not the overall amount. Indeed, during the postdeprivation period, the mean daytime (0800–2200 h) levels of IL-6 were significantly higher (P < 0.05), whereas the nighttime (2200–0600 h) levels were lower than the predeprivation values. Thus, sleep-deprived subjects had daytime oversecretion and nighttime undersecretion of IL-6; the former might be responsible for their daylong somnolence and fatigue, the latter for the better quality (depth) of their sleep. These data suggest that a good night’s sleep is associated with decreased daytime secretion of IL-6 and a good sense of well-being and that good sleep is associated with decreased exposure of tissues to the proinflammatory and potentially detrimental actions of IL-6. Sleep deprivation increases daytime IL-6 and causes somnolence and fatigue during the next day, whereas postdeprivation decreases nighttime IL-6 and is associated with deeper sleep.

	Introduction

Top Abstract Introduction Subjects and Methods Results Discussion References

 
RECENTLY, we demonstrated that inflammatory cytokines, including interleukin-6 (IL-6) and tumor necrosis factor , were elevated in disorders of excessive daytime sleepiness (EDS), i.e. sleep apnea and narcolepsy, and suggested that these cytokines might play a significant role in mediating the sleepiness and fatigue of these disorders (1). Sleep deprivation is associated with daytime sleepiness the next day in humans. Also, sleep deprivation seems to result in decreased cortisol secretion the next day (2), whereas acute glucocorticoid deficiency is associated with elevations of circulating IL-6 (3). Based on these findings, we hypothesized that IL-6 levels may be elevated the day after sleep deprivation and that this might play a role in mediating experimentally-induced daytime sleepiness in humans.

In our previous study, we also demonstrated that, both in patients with EDS and in controls, the morning levels of IL-6 were negatively correlated with the amount of the previous night’s sleep time (ST) (1). Yet, the relation between 24-h secretion of IL-6 and quantity and depth of sleep in young healthy men remains unknown. We hypothesized that an overall decreased secretion of IL-6 would be associated with a better quantity and depth of sleep in healthy volunteers. To test the above hypothesis we examined the relation between circadian IL-6 secretion and quantity and depth of sleep at baseline and after a night of total sleep deprivation.

	Subjects and Methods

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Subjects

Eight young healthy men, 20–29 yr of age (mean ± SE, 23.6 ± 1.0), with a body mass index of 25.6 ± 0.8, were recruited from the community and from the medical and technical staff and students of the Milton S. Hershey Medical Center. They were in good general health, physically active but not excessively so, had no sleep complaints or circadian abnormalities, were not taking any medications, and were screened in the Sleep Laboratory for sleep disordered breathing, nocturnal myoclonus, or other primary sleep disorders. Also, a battery of clinical tests (including complete cell blood count, urinalysis, thyroid indices, and electrocardiogram) were negative for abnormal findings.

Protocol

Each subject participated in a sleep deprivation experiment that lasted 7 days. After four consecutive nights in the Sleep Laboratory (1 adaptation night and 3 baseline nights), the subjects were deprived of sleep during the entire fifth night, and they were allowed to sleep again on nights 6 and 7. The subjects stayed awake in the presence of nursing or technical staff, and total wake time (TWT) before the first recovery night was 40 h. Twenty-four-hour blood sampling was performed serially every 30 min on the fourth day (predeprivation) and sixth day, the latter immediately after sleep deprivation. An indwelling catheter was inserted in the antecubital vein about 30 min before the first blood draw. The catheter was kept patent with small amounts of heparin. During the sleep recording period, blood was collected outside the subjects’ room through a perforation in the wall, via extended tubing, to decrease sleep disturbance from the blood drawing. During the day, blood samples were drawn in the Clinical Research Center of the University Hospital of the Milton S. Hershey Medical Center. Throughout sampling, the subjects were ambulatory, and they were allowed to watch TV, play computer and table games, go to the bathroom, and engage in other similar activities. Also, they were instructed not to change their diet, and their three daily meals were at about 0700, 1200, and 1800 h. The protocol was approved by the Institutional Review Board, and each subject signed a written consent form.

Sleep recordings

Sleep laboratory recording was carried out in a sound-attenuated, light- and temperature-controlled room that has a comfortable bedroom-like atmosphere. During this evaluation, each subject was monitored continuously for 8-h (2200–0600 h). The sleep schedule in the sleep laboratory was similar to the subjects’ normal sleep schedule. Electroencephalographic, electrooculographic, and electromyographic recordings were obtained in accordance with standard methods (4). The sleep recordings were amplified using standard clinical polygraphs (Grass Instrument Co., Model 78d&e, Quincey, MA). The sleep records were scored independently of any knowledge of the experimental condition, according to standardized criteria (4).

Sleep parameters, assessed from the sleep recordings, included sleep induction (sleep latency, or SL); sleep maintenance (wake time after sleep onset, or WTASO); TWT, which is the sum of SL and WTASO; total ST and percent ST (which is total ST, as percent of time in bed; percentage of the various sleep stages [rapid eye movement (REM), 1, 2, 3, and 4 combined slow wave sleep (SWS), which is calculated as the minutes in each stage as the percent of total ST; and REM latency, which is the interval from sleep onset to the first REM period]. Also, subjects were asked to rate their daytime sleepiness on a visual-analogue scale before and after sleep deprivation.

Hormone assays

Blood collected from the indwelling catheter was transferred to a heparinized tube and refrigerated until centrifugation (within 3 h). The plasma was frozen at -70° until assay. IL-6 was measured every hour by enzyme-linked immunosorbent assay (R and D systems, Minneapolis, MN). The intra- and interassay coefficients of variation for IL-6 were from 3.2–8.5% and 3.5–8.7%, and the lower detection limit was 0.094 pg/mL.

Statistical analyses

Twenty-four-hour serial plasma IL-6 levels were analyzed using MANOVA [mixed effects model with fixed effects being time and condition (pre- vs. postsleep deprivation) and random effects being the subjects], followed by the Dunnett post hoc test. Also, the mean levels of IL-6 over 24 h and during the daytime (0800–2200) and nighttime (2200–0600) periods, before and after sleep deprivation, were compared with repeated-measures ANOVA. Furthermore, the circadian rhythmicity of IL-6 secretion was assessed with cosinor-multiple-components rhythmometry (5), by fitting a curve to each individual profile and the entire population profile. This method allowed fitting a model with several cosine functions to the data. The data were analyzed after they were transformed to percent of the mean, which is the preferred approach to show predictable variability when data are obtained from different individuals (6).

To assess a potential relation between amount and depth of sleep and 24-h IL-6 secretion we calculated (using the Pearson product-moment correlation) correlations between mean total ST and percent SWS from nights 2 and 3 and 24-h, daytime (0800–2200), and nighttime (2200–0600) IL-6 levels pre deprivation. Also, to evaluate potential effects of amount and depth of sleep in the changes of IL-6 level postsleep deprivation, we calculated correlations between total ST and percent SWS and change of mean IL-6 plasma levels between pre- and post deprivation during the 24-h, daytime, and nighttime periods.

	Results

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Baseline IL-6 secretion and amount and depth of sleep

At baseline, IL-6 was secreted in a biphasic circadian pattern, with two nadirs at 0800 and 2100 h and two zeniths at 1900 and 0500 h (Fig. 1). Cosinor analyses, both for the individual and population IL-6 data, indicated a significant circadian rhythm, with a multiple component curve including periods with 12 and 24 h (P < 0.01; Fig. 2). Correlation analyses between baseline IL-6 plasma levels and polysomnographic indices of amount and depth of sleep showed a significant negative correlation between total ST and daytime (0800–2200 h) plasma IL-6 levels (P < 0.05), whereas there was no significant correlation between daytime IL-6 levels and percent SWS (see Table 2 and Fig. 3).

View larger version (20K): [in this window] [in a new window]   Figure 1. Twenty-four-hour plasma IL-6 concentrations pre- and post sleep deprivation in eight healthy young men. Each data point represents the mean ± SE. *, P < 0.05 indicates statistical significance from the peak value within 24 h for each condition (MANOVA followed by Dunnett post hoc test). The darkened area indicates the sleep recording period.

View larger version (16K): [in this window] [in a new window]   Figure 2. Cosinor-population multiple-component analysis at baseline showed a significant circadian rhythm of IL-6 with a multiple component curve, including periods of 24 and 12 h (top) (P < 0.01). The same model remained borderline significant (P = 0.058) post deprivation but with a significant (P < 0.01) shift of the major peak from 0500 to 1900 h (bottom). The darkened area indicates the sleep recording period.

View larger version (12K): [in this window] [in a new window]   Figure 3. Correlation between baseline quantity of sleep (total ST) and daytime IL-6 secretion. Total ST was based on nights 2 and 3.

Subjects demonstrated significantly shorter SLs in the postdeprivation than the baseline predeprivation nights (Table 1). Also, SWS was significantly longer post deprivation than pre deprivation. Finally, the subjects reported significantly higher levels of daytime sleepiness postdeprivation compared with baseline (P < 0.05).

Sleep deprivation changed significantly the circadian pattern of IL-6 secretion but not the overall amount (Fig. 1). Whereas the nadirs remained temporally and quantitatively the same in the sleep-deprived subjects, the evening zenith at 1900 h was twice, and night zenith at 0500 about half, of that in the baseline state. Cosinor analysis showed a borderline statistically significant circadian rhythm, with two peaks occurring at 1900 and 0500 h (P = 0.058; Fig. 2). However, compared with baseline, there was a significant shift of the major peak from 0500 to 1900 h (P < 0.01). The mean daytime (0800–2200 h) levels of IL-6 postdeprivation were significantly higher than the predeprivation values (P < 0.05), whereas the nighttime (2200–0600 h) levels of IL-6 postdeprivation were lower than the predeprivation values (nonsignificant). Also, the amount of slow wave (deep) sleep was negatively correlated to changes of IL-6 daytime plasma levels between post- and pre deprivation (P < 0.05), whereas there was no significant correlation between percent ST and difference of IL-6 levels post- and pre sleep deprivation (Table 2 and Fig. 4).

View larger version (13K): [in this window] [in a new window]   Figure 4. Differences (post- minus presleep deprivation) in daytime IL-6 plasma levels (pg/mL), compared with baseline depth of sleep (percent SWS). Percent SWS was based on nights 2 and 3.

	Discussion

Top Abstract Introduction Subjects and Methods Results Discussion References

Total sleep deprivation resulted in a significant shift of the circadian secretion of IL-6 in healthy humans, with daytime oversecretion and nighttime undersecretion of IL-6, compared with baseline. The increased secretion of IL-6 during the day after sleep deprivation might contribute to the subjects’ daylong somnolence and fatigue, whereas the nighttime undersecretion might explain their deeper sleep. Our finding on the association between oversecretion of IL-6 and daytime sleepiness after experimental sleep deprivation extends our previous results on the potential role of IL-6 in mediating sleepiness in disorders associated with EDS, e.g. sleep apnea (1). That a recent study did not demonstrate a significant change in IL-6 concentrations after sleep deprivation is probably attributable to infrequent sampling (every 3 h) and possibly a less sensitive assay (8).

At baseline, IL-6 was secreted in a biphasic circadian pattern, with two nadirs at 0800 and 2100 h and two zeniths at 1900 and 0500 h, with the stronger peak at 0500 h. This pattern changed after sleep deprivation only quantitatively, with IL-6 levels peaking at 1900 instead of 0500 h at baseline. Previous studies noted the circadian pattern of IL-6 secretion and its late-night peak (9, 10, 11). That these studies did not report on the daytime zenith of IL-6 at about 1900–2000 h could be attributable to their using infrequent sampling (9) or a small number of subjects (10, 11).

Lavie reported that sleepiness in young healthy humans, both at baseline and after sleep deprivation, is distributed in a bimodal fashion, with a major nocturnal sleepiness crest and a secondary daytime (afternoon) sleepiness peak (12). These peaks of sleepiness were separated by a so-called forbidden zone, for sleep centered around 2000–2200 h. In our study, the circadian secretion of IL-6, both at baseline and post deprivation, resembles closely the temporal pattern of sleepiness, including a drop, 2 h before sleep onset, suggesting that IL-6 might be a sleepiness mediator.

Do our data suggest that IL-6 is a sleep factor in humans and that its secretion is consistent with the homeostatic model of accumulation of sleep toxins during wakefulness (13, 14)? The increased plasma IL-6 levels during daytime after prolonged wakefulness and the decreased nocturnal levels during the recovery night (which is associated with increased SWS) and the correlation between daytime plasma levels of this cytokine with the preceding night’s sleep quantity and depth tend to support such a view. It seems, thus, that IL-6 secretion is influenced both by homeostatic and circadian factors (15).

The view that IL-6 is involved in sleep regulation is further supported by the finding that exogenous administration of IL-6 in healthy humans was associated with an increase of SWS in the second half of the night, suggesting a direct action of IL-6 on central nervous system sleep mechanisms (16). The sleep-disturbing effect of exogenous IL-6 noted in the first half of the night might be attributed to increased secretion of ACTH and cortisol, during the early part of the night, induced by IL-6. An alternative, not mutually exclusive, hypothesis is that high levels of IL-6 may compromise early nighttime sleep. Such a hypothesis is consistent with the results of our study showing that recovery sleep, which was deeper than baseline, was associated with reduced IL-6 levels.

The relation between IL-6 secretion and quantity and depth of sleep may have several physiologic and pathophysiologic implications. For example, it is known that normal aging is associated with decreased quantity and quality of sleep (17) and increased secretion of IL-6 (18). We speculate that the poor quantity and quality of sleep in the elderly may, through hypersecretion of IL-6, contribute to common ailments associated with old age, i.e. osteoporosis, cardiovascular complications, and others (7, 19). Also, sleep deprivation or shift work, common in industrialized societies, is associated with sleep disturbance, fatigue, sleepiness, and potentially catastrophic accidents. The association, reported in our study, between quantity and depth of sleep, sleep loss and circadian secretion of IL-6, may lead to a better management of those individuals who are unable to tolerate sleep loss and to a more medically-based approach to these significant problems.

In conclusion, the results of our study suggest that IL-6 may play an important role both in sleep regulation and experimentally induced sleepiness, albeit possibly through different mechanisms. Additional studies, including the assessment of the circadian secretion of IL-6 in experimental and pathological conditions and use of neutralizing IL-6 antibodies to decrease pathological and experimental sleepiness, are needed to establish firmly the role of this cytokine in sleep and sleepiness in humans.

	Acknowledgments

 
We thank the nursing staff of the General Clinical Research Center at the Penn State College of Medicine for their technical assistance and Barbara Green for her assistance in word processing and overall preparation of the manusript.

Received September 4, 1998.

Revised April 2, 1999.

Accepted April 30, 1999.

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