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Max Planck Institute of Psychiatry, D-80804 Munich, Germany
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ABSTRACT |
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 TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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Numerous animal studies suggest that
cytokines such as interleukin-1
(IL-1) and tumor necrosis
factor-
(TNF-) mediate increased sleep amount and intensity
observed during infection and are, moreover, involved in physiological
sleep regulation. In humans the role of cytokines in sleep-wake
regulation is largely unknown. In a single-blind, placebo-controlled
study, we investigated the effects of granulocyte colony-stimulating
factor (G-CSF, 300 µg sc) on the plasma levels of cytokines, soluble
cytokine receptors, and hormones as well as on night sleep. G-CSF did
not affect rectal temperature or the plasma levels of cortisol and
growth hormone but did induce increases in the plasma levels of IL-1
receptor antagonist and both soluble TNF receptors within 2 h after
injection. In parallel, the amount of slow-wave sleep and
electroencephalographic delta power were reduced, indicating a lowered
sleep intensity. We conclude that G-CSF suppresses sleep intensity via
increased circulating amounts of endogenous antagonists of IL-1 and
TNF- activity, suggesting that these cytokines are involved in human sleep regulation.
tumor necrosis factor-; interleukin-1; soluble tumor necrosis
factor receptors; interleukin-1 receptor antagonist; non-rapid eye
movement sleep
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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IT IS WELL ESTABLISHED that cytokines like
interleukin-1 (IL-1) and tumor necrosis factor- (TNF-) are
pivotal mediators in the adaptive changes of central nervous system
(CNS) function during infection and inflammation. The role
of cytokines has been explored with respect to the induction of fever
(15) and the activation of the hypothalamic-pituitary-adrenal system
(36). Furthermore, changes in sleep and wakefulness during host defense activation have been reported. In various animal models, the most consistent effects of bacterial, viral, and fungal infections on sleep
are increases in the amount of non-rapid eye movement (non-REM) sleep
and electroencephalographic (EEG) delta activity thought to reflect
enhanced sleep intensity (34). Convincing evidence suggests that
infections influence sleep by inducing the release of cytokines such as
IL-1 and TNF- (17). Moreover, it has been postulated that
cytokines are involved in physiological sleep-wake regulation
independent of infection and inflammation. This view is supported by
animal studies showing that the amount of non-REM sleep and EEG delta
activity are suppressed when the biological activity of IL-1 (22) or
TNF- (32) is antagonized.
The present knowledge about the influence of host defense activation on
sleep in humans relies mainly on the effects of intravenous injection
of endotoxin, the major cell wall component of gram-negative bacteria.
Endotoxin administration is a well-established model of host defense
activation (2), which, besides its immunologic effects, has also been
shown to alter sleep in healthy volunteers (13, 16, 21, 25). It is
likely that endotoxin-induced changes in sleep-wake behavior are
mediated by cytokines such as TNF- or IL-6, which recently also have
been shown to affect sleep in healthy subjects (29). However, it
remains unclear whether these cytokines exert their effects on sleep
regulation by themselves or through their influence on other
physiological systems that affect sleep, like temperature regulation
(9) or endocrine systems, e.g., the hypothalamic-pituitary-adrenal (4)
and the hypothalamic-somatotropic systems (30). Furthermore, it is not
known whether cytokines are involved in physiological sleep regulation
in humans.
We recently have shown that granulocyte colony-stimulating factor
(G-CSF), which is well known for its stimulating effects on
granulopoiesis and granulocyte function (31), induces subtle increases
in the circulatory levels of TNF-, soluble TNF receptors (sTNF-R)
p55 and p75, and interleukin-1 receptor antagonist (IL-1Ra) but does
not influence the plasma levels of IL-1 or IL-6 or rectal body
temperature in healthy volunteers (24). Therefore, the administration
of G-CSF offers the possibility of investigating the influence of
subtle alterations in immunologic homeostasis on sleep, whereby body
temperature and endocrine systems remain unaffected. A respective
placebo-controlled investigation in healthy humans is presented in this study.
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MATERIALS AND METHODS |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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Subjects and experimental procedure. The experimental procedure was approved by the Ethics Committee for Human Experimentation at the Max Planck Institute of Psychiatry. Ten healthy male volunteers (mean age 25.4 yr, range 21-35 yr) took part after written informed consent was obtained. They were screened by medical history, physical examination, laboratory investigations, electrocardiogram, and electroencephalogram to exclude acute and chronic illness as well as substance abuse.
G-CSF (Neupogen), purchased from Hoffmann LaRoche (Grenzach, Germany),
was administered in a single-blind, placebo-controlled crossover
design. In balanced order, either 300 µg G-CSF in 500 µl of 0.9%
saline solution or 500 µl pure saline solution were injected
subcutaneously at 2100 during two experimental sessions separated by 2 wk. Both sessions were preceded by an adaption night so that the
volunteers could become accustomed to the sleep laboratory conditions.
The physical examination and laboratory screening tests were repeated
after the adaption night to exclude acute infection. During the
following day the subjects were offered calorie- and
electrolyte-balanced meals at 1200 and 1730. At 1830 an intravenous
cannula was placed in an antecubital forearm vein, and blood was
sampled intermittently until 0700 the next morning (Figs. 1-3).
The blood was stabilized with Na-EDTA (1 mg/ml blood) and aprotinin
(300 KIU/ml blood). The plasma was frozen to 
20°C after
being centrifuged and aliquoted. Additional blood samples were taken
intermittently for white blood cell counts. Blood pressure was measured
until 2300 with a Dinamap Vital Daten Monitor 1846SX (Critikon,
Norderstedt, Germany), whereas a one-lead electrocardiogram and rectal
temperature (temperature monitor model 8055, S & W, Albertslund,
Denmark) were monitored throughout the entire experimental session. The
subjects were under continuous observation, and a physician was
permanently on call.
Polygraphic monitoring of sleep according to Rechtschaffen and Kales (26) was started at 2300 and stopped 8 h later, when the subjects were awakened. The EEG (C3-A1; C4-A2) was recorded with a high-pass filter at 0.53 Hz and a notch filter at 50 Hz and calibrated at 50 µV with a 10.0-Hz sine wave. The biosignals were digitized at 97.1 Hz and stored on magnetic tape. All technical equipment was located in a room adjacent to the sound-shielded sleep laboratory.
Data analysis. One subject had to be excluded from the data analysis because of a positive urine screening test for amphetamines obtained before the second experimental session. The sleep recordings were scored visually in 30-s epochs according to Rechtschaffen and Kales (26). The scorers were unaware of the treatment condition. EEG spectral analysis was done using a fast Hartley transformation algorithm, and power spectra were computed for rectangular windows of 256 samples, corresponding to an epoch length of 2.63 s. The frequency resolution was 0.38 Hz, with frequencies between 0.53 and 19.0 Hz being analyzed. The EEG spectral power of the delta (0.76-4.18 Hz), theta (4.54-7.98 Hz), alpha (8.36-11.78 Hz), sigma (12.26-14.44 Hz), and beta (14.82-18.62 Hz) frequency bands were computed for combined non-REM sleep stages 2, 3, and 4. The analysis was restricted to artifact-free visually scored epochs. A more detailed methodological description of the spectral analysis was published earlier (35).
Blood cell counts and hormone and cytokine
assays. Blood cell counts were determined with a
Coulter counter ST3 (Coulter, Krefeld, Germany). Commercial
enzyme-linked immunosorbent assays (Medgenix Diagnostics, Brussels,
Belgium) were used to determine TNF- and sTNF-R p55 and p75 plasma
levels. IL-1Ra plasma levels were also determined by ELISA (R & D
Systems, Minneapolis, MN). The intra- and interassay coefficients of
variation were below 5% and 8%, respectively, for all these assays.
For TNF- we added an additional standard of 4.3 pg/ml to optimize
sensitivity. The detection limits for the assays (in pg/ml) were 3 for
TNF-, 50 for sTNF-R p55, 100 for sTNF-R p75, and 22 for IL-1Ra.
Plasma cortisol (ICN Biomedicals, Carson, CA) and human growth hormone (hGH; Nichols Institute Diagnostics, San Juan Capistrano, CA) plasma
levels were determined using coated tube RIAs. The limit of detection
(in µg/l) was 0.2 for cortisol and 1.5 for hGH, and the intra- and
interassay coefficients of variation were <7%.
Statistical methods. Commercially available personal computer software (SPSS for Windows 6.1.3) was used to perform data analysis. Differences in the time courses of parameters between placebo and verum conditions were analyzed by ANOVA for repeated measures. The paired Student's t-test was used for post hoc comparison, two-sided P values were reported, and P < 0.05 was considered significant. All data reported in the text and Tables 1 and 2 are means ± SD; in Figs. 1-4, means ± SE are given.
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RESULTS |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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Effects of G-CSF on heart rate, rectal temperature,
and the plasma levels of cortisol and growth hormone.
No subjective side effects of G-CSF treatment occurred. In particular,
no subject reported musculoskeletal pain. Using ANOVA for repeated
measures, we detected no significant time-by-treatment interaction
effect for heart rate, body temperature, or the plasma levels of
cortisol or hGH (Fig. 1). There was no
significant treatment effect for the plasma levels of cortisol
[F(1,8) = 0.84, P = 0.385] or hGH [F(1,8) = 0.17, P = 0.693], but there was for
heart rate [F(1,8) = 10.22, P = 0.013] and body temperature
[F(1,8) = 6.52, P = 0.034]. However, as shown in
Fig. 1, both heart rate and rectal temperature differed between
conditions already at baseline, suggesting that the observed slight
difference was not G-CSF induced. This was confirmed by an ANOVA
performed on normalized values (for this purpose all values in each
group were expressed as percentage of the mean at 2100), which did not
reveal significant condition effects for heart rate
[F(1,8) = 1.72, P = 0.225] or rectal temperature [F(1,8) = 0.01, P = 0.942].
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Effects of G-CSF on white blood cell counts and
cytokine and soluble cytokine receptor plasma levels.
ANOVA for repeated measures revealed significant time-by-condition
interaction effects for total white blood cell, granulocyte, monocyte,
and lymphocyte counts and the plasma levels of TNF-, sTNF-R p55 and
p75, and IL-1Ra (Figs. 2 and
3). There were significant treatment effects on total
white blood cell [F(1,8) = 67.76, P < 0.001], granulocyte [F(1,8) = 53.38, P < 0.001], and monocyte
counts [F(1,8) = 8.76, P < 0.01], but not on
lymphocyte counts [F(1,8) = 0.65, P = 0.443]. ANOVA also
revealed significant treatment effects on the plasma levels of TNF-
[F(1,8) = 5.93, P < 0.05], sTNF-R
p55 [F(1,8) = 114.20, P < 0.001], sTNF-R p75
[F(1,8) = 79.60, P < 0.001], and IL-1Ra
[F(1,8) = 70.88, P < 0.001].
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Total white blood cell and granulocyte counts decreased rapidly to a
nadir 30 min after the injection of G-CSF but increased significantly
thereafter until the end of the night. Monocyte and lymphocyte counts
did not increase significantly before 0700. The plasma levels of
IL-1Ra, TNF-, and sTNF-R p55 and p75 all increased in response to
G-CSF treatment; compared with placebo, soluble TNF receptors and
IL-1Ra plasma levels were significantly elevated from 2300 onward. In
contrast, G-CSF-induced increases of TNF- plasma levels were not
significant until 8 h after injection. Hence, at the time of sleep
onset, the plasma levels of IL-1Ra and sTNF-R p55 and p75, but not
those of TNF-, were all significantly increased in response to G-CSF administration.
Effects of G-CSF treatment on sleep.
There were no significant differences between conditions with respect
to subjective tiredness before and after injection and in self-rated
sleep quality reported the following morning (data not shown). G-CSF
caused a significant increase in sleep period time, REM sleep latency,
and the amount of movement time but caused no significant changes in
the amounts of the different sleep stages (Table
1) or spectral EEG power (data
not shown) when the entire night was considered.
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To account for the temporal pattern of G-CSF-induced increases in the
plasma levels of cytokines and soluble cytokine receptors, we analyzed
the time course of night sleep in 2-h blocks (Table 2); ANOVA for repeated measures revealed
significant time-by-condition interaction effects only for the amounts
of stage 3 non-REM sleep [F(3,6) = 18.45, P = 0.002] and
slow-wave sleep [F(3,6) = 5.60, P = 0.036]. Post hoc comparison
revealed a significant decrease in slow-wave sleep during the first 2-h
block of time in bed after G-CSF administration. The mean amounts of
stage 3 and stage 4 non-REM sleep were both reduced during these 2 h,
but only the decrease in stage 3 sleep was statistically significant.
During the same 2-h block, non-REM sleep total EEG power (430 ± 120 vs. 540 ± 180 µV2,
P < 0.05) and delta power (370 ± 110 vs. 480 ± 160 µV2,
P < 0.05) were significantly
reduced. This was the result of a significant reduction of EEG power in
the frequency bins between 0.76 and 6.08 Hz, covering lower theta and
delta frequencies (Fig. 4). However, EEG
power for the entire theta band and the alpha, sigma, and beta bands
was not significantly altered by G-CSF (data not shown). During the
last 2-h block, mean stage 3 non-REM sleep amount was enhanced after
G-CSF, but this effect showed only a trend toward statistical
significance (P = 0.052). In parallel, mean EEG power in the delta frequency band was increased (Fig. 4).
However, the difference between conditions was not significant.
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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In the present study, we examined the effects of G-CSF on night sleep
and various hematologic, immunologic, and endocrine variables, as well
as on rectal temperature in healthy volunteers. The hematologic effects
of G-CSF, including an initial decrease followed by a prominent
increase in granulocyte counts and slight increases in monocyte and
lymphocyte counts, are in line with earlier reports (for review see
Ref. 1). For the first time we have been able to show that a single
dose of G-CSF does not influence the plasma levels of hGH and cortisol.
The present study confirms earlier observations that G-CSF does not
influence rectal temperature but increases the plasma levels of
TNF-, sTNF-R p55 and p75, and IL-1Ra (24). Because of a higher time
resolution, we are able to show here that the G-CSF-induced increases
in the plasma levels of IL-1Ra and soluble TNF receptors precede the increase in plasma TNF- levels by several hours. We showed earlier that G-CSF influences neither the plasma levels of IL-1 nor those of
IL-6 (24).
G-CSF had only minor effects on night sleep as a whole but had a
distinct influence on its time course; during the first 2 h of night
sleep, in parallel with steep increases in the plasma levels of IL-1Ra
and both soluble TNF-receptors but before significant increases in
TNF- plasma level, the amount of slow-wave sleep, in particular
non-REM sleep stage 3, and EEG delta power were decreased by ~20%.
During the last 2 h of the night, when TNF- levels were
significantly increased, stage 3 non-REM sleep and EEG-delta power were
tendentially, but not significantly, increased.
In summary, a single dose of G-CSF induced a distinct temporal pattern
of increases in the systemic concentrations of cytokines and soluble
cytokine receptors and altered the time course of night sleep but did
not affect body temperature, heart rate, or major neuroendocrine
systems. Hence, the effects of G-CSF on sleep cannot be attributed to
influences on a number of physiological systems pivotal for the
regulation of sleep and wakefulness, such as the
hypothalamic-pituitary-adrenal (4) and the hypothalamic-somatotropic endocrine systems (30), or body temperature (9). Therefore, the effects
of G-CSF on night sleep can best be explained either by direct effects
of this cytokine on the brain or by G-CSF-induced changes in the
systemic concentrations of TNF-, soluble TNF receptors, or IL-1Ra.
Until now, no effects of G-CSF on CNS function have been reported.
Although there is preliminary evidence that intracerebroventricular administration of granulocyte-macrophage CSF and macrophage CSF alters
sleep in rats (14), there are no data so far to support the idea that
systemic administration of any CSF directly affects the brain. However,
it is well established that systemic administration of inflammatory
cytokines influences CNS function through various pathways (for review
see Ref. 27). Additionally, numerous animal studies suggest an
involvement of the TNF and IL-1 cytokine systems in sleep regulation;
it has been shown that intracerebroventricular administration of
IL-1 (10, 18, 33) and TNF- (12, 28) promotes non-REM sleep and
EEG delta power in animals, whereas the administration of IL-1Ra (10,
22) and sTNF-R p55 (32), but not sTNF-R p75 (19), has the opposite
effect. Recent evidence also suggests that systemic administration of
TNF- exerts these effects on sleep through the TNF-receptor p55;
Fang et al. (3) showed that sTNF-R p55 knockout mice
showed a reduced spontaneous amount of non-REM sleep that did not
increase after intraperitoneal administration of TNF-. This increase
was nevertheless observed in wild-type control animals.
The results of the present study fit well within the framework of these
animal data: the temporal association of steep G-CSF-induced increases
in the plasma levels of sTNF-R p55 and IL-1Ra occurring without a
concomitant increase in the plasma levels of TNF- and IL-1 on the
one hand, and a reduction in the amount of slow-wave sleep and delta
power during the first 2 h of sleep on the other hand, is in accordance
with the idea that increased concentrations of antagonists of
inflammatory cytokine actions suppress non-REM sleep, possibly by
antagonizing non-REM sleep-promoting effects of endogenous TNF- or
IL-1, or both. During the last 2 h of night sleep, there was, along
with increased circulating TNF- levels, a trend toward increased EEG
delta power and stage 3 non-REM sleep, further supporting the view that
even very small changes in systemic TNF- and sTNF-R levels affect
non-REM sleep.
In humans, TNF- is present in the circulation under baseline
conditions in detectable, albeit small, amounts (16, 24, 25).
Therefore, it seems reasonable to assume an involvement of circulating
TNF- in non-REM sleep regulation under physiological conditions in
humans. Non-REM sleep suppression by increased levels of soluble TNF
receptors may then be explained by an increased complexing of the
cytokine to soluble receptors, which causes a decreased active
transport of TNF- to the brain, as has been described in mice (6).
In contrast, there is no consistent evidence so far that IL-1
circulates under baseline conditions in humans (24, 25). However, this
does not exclude the presence of relevant amounts of IL-1 in the
CNS. Therefore, increased circulating amounts of IL-1Ra after G-CSF
administration may antagonize IL-1 effects on sleep-wake regulation
after an active transport of the cytokine receptor antagonist to the
brain, as also has been documented in mice (7).
In summary, our results provide for the first time evidence in humans that very subtle changes in the systemic concentrations of cytokines and soluble cytokine receptors that are not accompanied by neuroendocrine activation or changes in body temperature alter sleep-wake behavior. To further delineate the role of the IL-1 and TNF cytokine systems in human sleep physiology, studies seem warranted that investigate the effects of IL-1Ra and sTNF-R p55 on sleep. IL-1Ra has already been shown to be well tolerated in healthy volunteers (5).
Perspectives
In addition to enhancing the understanding of sleep regulation, further studies on the effects of immunomodulation on human sleep may open new avenues for the development of treatments for disordered sleep-wake behavior. It may even be that sedative compounds that are already used in clinical practice exert their effects on sleep through immunomodulation. Recently, the antipsychotic drug clozapine has been shown to consistently induce slight increases in the plasma levels of TNF- and both soluble TNF receptors (23). These properties of
clozapine may be involved in the drug's effects on sleep (8, 37).
There are other sedative drugs that influence cytokine secretion, such
as, for example, thalidomide, a sedative drug and powerful
immunomodulator (39) that, because of its teratogenic effects, is no
longer used as a hypnotic. In vitro thalidomide was shown to inhibit
TNF- synthesis (20). In vivo, however, two studies observed slight
increases in the circulating plasma levels of TNF- that are
comparable to those observed after clozapine treatment (11, 38).
Therefore, the immunomodulatory effects of sedating drugs deserve
intensive further experimental investigation.
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ACKNOWLEDGEMENTS |
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We thank Irene Gunst and Gaby Kohl for excellent technical assistance.
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FOOTNOTES |
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This study was supported by Grant I/71979 from the Volkswagen-Stiftung (Hannover, Germany).
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. §1734 solely to indicate this fact.
Address for reprint requests and other correspondence: T. Pollmächer, Max Planck Institute of Psychiatry, Kraepelinstrasse 10, D-80804 Munich, Germany (E-mail: topo{at}mpipsykl.mpg.de).
Received 17 October 1998; accepted in final form 4 January 1999.
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
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