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on sleep are mediated by the type
I receptor
Department of Physiology and Biophysics, University of Tennessee, Memphis, Tennessee 38163
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ABSTRACT |
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Top
Abstract
Introduction
Methods
Results
Discussion
References
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Interleukin-1
(IL-1) is a well
characterized sleep regulatory substance. To study receptor mechanisms
for the sleep-promoting effects of IL-1, sleep patterns were
determined in control and IL-1 type I receptor knockout (IL-1RI KO)
mice with a B6x129 background after intraperitoneal injections of
saline or murine recombinant IL-1. The IL-1RI KO mice had slightly
but significantly less sleep during the dark period compared with the
controls. IL-1 dose dependently increased non-rapid eye movement
sleep (NREMS) and suppressed rapid eye movement sleep (REMS) in the
controls. The IL-1RI KO mice did not respond to IL-1. In contrast,
the IL-1RI KO mice increased NREMS and decreased REMS after
administration of tumor necrosis factor-
(TNF-), another well
characterized sleep-promoting substance. These results
1) provide further evidence that
IL-1 is involved in sleep regulation,
2) indicate that the effects of
IL-1 on sleep are mediated by the type I receptor, and
3) suggest that TNF- is capable
of inducing sleep without the involvement of IL-1.
interleukin-1 receptor; knockout mice; tumor necrosis factor
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INTRODUCTION |
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Top
Abstract
Introduction
Methods
Results
Discussion
References
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INTERLEUKIN-1 (IL-1) is one of the best
characterized sleep-promoting substances. Administration of exogenous
IL-1 increases non-rapid eye movement sleep (NREMS) in all species
tested, including rabbits (26), rats (38, 49), cats (43), mice (19),
and monkeys (20), and induces sleepiness in humans (12).
In contrast, reduction of endogenous IL-1 activity by administration
of anti-IL-1 antibodies (36), the IL-1 receptor antagonist (37), or the IL-1 soluble receptor (45) inhibits spontaneous sleep or sleep induced
by sleep deprivation. The IL-1 receptor antagonist or the IL-1 soluble
receptor also inhibits sleep induced by bacterial products (46).
Furthermore, sleep is enhanced by substances that stimulate IL-1
production such as muramyl dipeptide, double-stranded RNA, and tumor
necrosis factor (TNF-) (reviewed in Ref. 25) and is reduced by
substances that inhibit IL-1 such as corticotropin-releasing hormone
(16), prostaglandin E2 (23),
interleukin-4 (27), and interleukin-10 (39). IL-1 and other members
of the IL-1 family of molecules are constituitively expressed in the
brain (reviewed in Ref. 25). IL-1 mRNA in the brain is increased during sleep deprivation (30) and displays a diurnal rhythm in the
hypothalamus, hippocampus, and cortex in rats (44). IL-1-like bioactivity in the cerebrospinal fluid also varies in phase with the
sleep-wake cycle (29). Finally, sleep deprivation increases circulating
IL-1 (24, 33).
Although the involvement of IL-1 in sleep regulation is well
characterized, the mechanisms responsible for such effects are not
clearly understood. This is in part due to the fact that the receptor
that mediates the effects of IL-1 on sleep was unknown. IL-1
receptors are classified into type I and type II receptors (10, 17).
The biological activities of IL-1 are thought to be mediated by the
type I receptor, whereas the type II receptor is thought to be a decoy
receptor with a truncated nonsignaling intracellular domain (9).
However, the type of receptor that is involved in sleep regulation had
not heretofore been determined. Currently, it is not possible to
differentiate the two types of IL-1 receptors using pharmacological
methods. The presence of mutant mice lacking the IL-1 type I receptor
provided an opportunity to study the receptor mechanisms of IL-1. These
mutant mice develop normally with no apparent anomalies. It was
therefore of interest to investigate sleep in these IL-1 type I
receptor knockout (IL-1RI KO) mice.
In the present experiment, we determined spontaneous sleep and whether
IL-1 induces sleep in IL-1RI KO mice. We now report that the IL-1RI
KO mice have slightly, but significantly, less sleep during the dark
period than their strain controls and do not exhibit sleep responses
after the administration of exogenous IL-1. In contrast, the IL-1RI
KO mice do retain the ability to express excess NREMS if given TNF-,
another well characterized NREMS-promoting cytokine.
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METHODS |
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Top
Abstract
Introduction
Methods
Results
Discussion
References
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Animals. Adult male IL-1RI KO mice (n = 14; 86.71 ± 2.44 days old, weighing 30.84 ± 0.87 g), which have a B6x129 background (a cross between a 129 strain in which the IL-1RI gene was knocked out and C57BL/6 mice), and B6x129-F2 control mice (n = 14; 84.71 ± 2.76 days old, weighing 32.37 ± 1.1 g) were used in the experiments. The IL-1RI KO mice were obtained from Immunex (Seattle, WA). Control mice were purchased from Jackson Labs (Bar Harbor, MA). Mice were anesthetized with ketamine (25 mg/kg) and xylazine (25 mg/kg) and implanted with three electroencephalogram (EEG) electrodes (Plastics One, Roanoke, VA) in the skull over the frontal and parietal cortices, and three electromyogram (EMG) electrodes in the muscles of the dorsal neck, respectively. The electrodes and the attached wires were fixed to the skull with dental cement. Ten to twenty days were allowed for the mice to recover from surgery. Mice were housed at 30 ± 1°C in separate recording cages in sound-attenuated environmental chambers with a 12:12-h light-dark cycle (lights on at 0500 and off at 1700).
Experimental protocol. Each mouse
received one (400 ng; n = 6 for controls and n = 7 for IL-1RI KO)
or two (25 and 100 ng; n = 8 for
controls and n = 7 for IL-1RI KO)
doses of recombinant murine IL-1 (from R & D Systems, Minneapolis,
MN) in a volume of 0.1 ml physiological saline by intraperitoneal
injections. Each IL-1 injection day was preceded by a saline
injection day. When mice were tested with two doses, the lower dose (25 ng) was tested first and there were at least 3 days without any
injection between the previous IL-1 injection and the next saline
injection. Two IL-1RI KO and one control mice lost their recording
electrodes after IL-1 injection. The data from these mice were only
included in the analyses of baseline sleep data. In a separate
experiment, IL-1RI KO mice (n = 7)
were also injected intraperitoneally with saline on a control day and
murine TNF- (R & D Systems; 1 µg/mouse) on an experimental day. In
all conditions, the injections were done at dark onset (1700).
Sleep recording. EEG and EMG were continuously recorded for 24 h after each injection. Sleep data were collected with a Grass polygraph (Grass Instruments, Quincy, MA). The EEG signals were amplified with a 7P5 wide band EEG preamplifier and a 7P-DA-G DC driver amplifier. The one-half cut-off for low and high frequencies was set at 0.5 and 35.0 Hz, respectively. The EMG signals were amplified with a 7P511J amplifier with one-half cut-off for low and high frequencies set at 100 and 10,000 Hz, respectively. The data collection was controlled by a 386 personal computer. The J6 output from the DC drivers or 7P511J amplifiers was fed into a 12-bit analog-to-digit (AD) converter (PC-30D, Omega Engineering, Stamford, CT). The AD converter digitized the EEG and EMG signals at 128 Hz. The digitized data were transferred to the computer memory and graphically displayed on the computer monitor. An on-line fast Fourier transformation (FFT) was performed on EEG data every 2 s. The FFT analyses generated power density values from 0.0 to 63.5 Hz at a 0.5-Hz resolution. The results of FFT were averaged for every 10 s. The sleep data and FFT results were saved to the hard disk for off-line analyses.
Sleep data were scored to determine behavioral states of the animals as previously described (18). After data collection, the EEG, EMG patterns, and FFT data were graphically displayed on the screen of a computer monitor for sleep scoring. The behavioral states were categorized visually according to the following criteria: wakefulness was identified by low-voltage and fast EEG waves and high-amplitude EMG; NREMS by high-voltage and low-frequency EEG and low-amplitude EMG; and rapid eye movement sleep (REMS) by low-voltage EEG with clear (6-10 Hz) theta activity and dramatic suppression of EMG with occasional muscle twitches. Sleep was scored in epochs of 10 s. The behavioral state assigned to each epoch was determined by the predominant state of the epoch. The number of epochs for wakefulness, NREMS, and REMS was calculated by a computer program based on the criterion that the minimal episode length for each state should last at least 30 s.
The FFT data were sorted by a computer program according to the scoring
results. The epochs containing movement artifacts were excluded from
analyses. The total power in each 5-Hz frequency band was summed for
each 10-s epoch and then averaged for every 6 h. Results from the 0.5- to 5.0-Hz frequency band are presented; these results are referred to
as EEG slow-wave activity (SWA). Since the EEG amplitude was subject to
the influences of subtle variations of EEG electrode placement, the
average power during NREMS on each saline injection day was normalized
to 100. The relative changes of EEG power from the baseline were
calculated for data collected after IL-1 or TNF- treatment.
Statistical analyses. Sleep and EEG spectrum data were analyzed with two-way analysis of variance (ANOVA) for repeated measures and followed by Student-Newman-Keuls (SNK) multiple comparison test. In all conditions, the level of statistical significance was set at P less than or equal to 0.05.
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RESULTS |
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Top
Abstract
Introduction
Methods
Results
Discussion
References
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Abnormal behaviors in IL-1RI KO mice were not apparent, although the behaviors were not systematically measured except for sleep and waking states. The EEG patterns in IL-1RI KO mice were also normal and did not differ from those of the control mice. Both control and IL-1RI KO mice had clear circadian variations of EEG SWA: increasing during the dark period and decreasing during the light period (Fig. 1).
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NREMS was decreased in the IL-1RI KO mice compared with the control mice during the dark period [260.81 vs. 299.13 min; F(1,26) = 9.14, P < 0.01 for group and time interaction; q(2,26) = 3.558, P < 0.05], but not the light period (Fig. 1). The reduction of NREMS in IL-1RI KO mice was more pronounced during the first half of the dark period (137.43 vs. 108.25 min) than during the second half (161.70 vs. 152.56 min). REMS was not significantly different between groups.
In control mice, IL-1 dose dependently increased NREMS and
suppressed REMS (Fig. 2). IL-1 had no
effect on sleep at the 25-ng dose and increased NREMS at 100-ng
[F(1,6) = 20.3, P < 0.005] and 400-ng
[F(1,5) = 11.02, P < 0.025] doses. The effects
of IL-1 on NREMS were time dependent, primarily found during the
first 6 h after injection. NREMS was increased after 100 ng IL-1
[126.62 vs. 193.29 min; F(3,18) = 11.5, P < 0.0002 for treatment and
time interaction; q(4,18) = 10.062, P < 0.05] and after 400 ng
IL-1 [148.64 vs. 265.97 min;
F(3,15) = 56.81, P < 0.0001 for treatment and time
interaction; q(8,15) = 15.87, P < 0.01] during the first 6 h
after injections. REMS was significantly decreased by 100 ng
[15.29 vs. 9.57 min; F(1,6) = 8.013, P < 0.03] and 400 ng
IL-1 [14.72 vs. 3.86 min;
F(1,5) = 516.65, P < 0.0001] during the first 6 h after injections. EEG SWA was significantly decreased after 400 ng
IL-1 [F(1,5) = 6.86, P < 0.05 for treatment
effects], but not after 25 or 100 ng IL-1. The decrease of EEG
SWA was primarily found during the first few hours after IL-1
injection [Fig. 2; F(3,15) = 3.88, P < 0.05 for treatment and
time interaction; q(5, 15) = 5.632, P < 0.05 for the first 6-h
period].
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Unlike the control mice, IL-1RI KO mice did not change sleep or EEG SWA
parameters after 25, 100, or 400 ng IL-1 (Fig. 2), except that REMS
was slightly increased after 25 ng IL-1 [107.56 vs. 119.23 min; F(1,4) = 8.541, P < 0.05]. In contrast, IL-1RI KO mice had robust increases in NREMS after 1 µg TNF- (Fig.
3) during the first 6 h after injection
[99.95 vs. 170.76 min; F(3,18) = 18.3, P < 0.0001 for treatment and
time interaction; q(4,18) = 11.596, P < 0.01] and during the 24-h
period after injection [601.66 vs. 684.00 min;
F(1,6) = 17.8, P < 0.01]. The same dose of
TNF- also caused a slight suppression of REMS during the 24-h period
after injection [103.35 vs. 92.51 min;
F(1,6) = 6.48, P < 0.05].
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DISCUSSION |
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Top
Abstract
Introduction
Methods
Results
Discussion
References
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The IL-1RI KO mice sleep less during the dark period than their strain
controls; this observation is consistent with our previous observations
that inhibition of endogenous IL-1 activity with anti-IL-1 antibody
or IL-1 soluble receptor inhibits spontaneous sleep (36, 46). Current
observations thus provide further evidence to support the idea that
endogenous IL-1 is involved in physiological sleep regulation. However,
the present result must be interpreted with great caution. The
B6x129-F2 mice were chosen as a control strain since this strain was
the background on which the IL-1RI KO mice were developed. However, the
genetic mix produced when selecting for a knockout strain is different from a random mix produced by crossing two lines (21). Therefore, we
cannot exclude the possibility that the observed sleep differences might be due to the alterations of other unknown factors during the
development of the IL-1R KO mice. In addition, the consequence of
permanent loss of the IL-1RI gene from the beginning of the development
might be very different from the results of temporal suppression of
IL-1 activity, since the animals might have developed compensatory
mechanisms for the loss of IL-1RI. Although we did not observe a
reduction of sleep in IL-1RI KO mice compared with control mice during
the light period in the present study, temporal inhibition of
endogenous IL-1 with anti-IL-1 antibodies indeed reduces
spontaneous sleep and sleep rebound after sleep deprivation during the
light period in rats (36), another nocturnal species. Furthermore, the
IL-1 mRNA levels in rat brain vary with circadian rhythm, being
highest in the beginning of light period (44). These observations
suggest that compensation for the loss of the IL-1 receptor exists
during the light period in IL-1RI KO mice.
Although abundant evidence indicates that IL-1 is an important
humoral agent involved in sleep regulation, the receptor mechanism for
its sleep-promoting effects was unknown. The present results show that
IL-1 dose dependently increased NREMS and suppressed REMS in control
mice. In contrast, the only effect of IL-1 on sleep in IL-1RI KO
mice was a slight increase in REMS at a 25-ng dose at
P < 0.05 level. Given the small
difference, the level of significance, and the number of statistical
tests in the study, it is likely that this effect was purely due to
chance.
Current observations provide strong evidence that the type I, but not
type II, IL-1 receptor, is involved in the sleep alterations induced by
IL-1. The involvement of the type I receptor in sleep regulation is
consistent with the current thinking that the type I receptor is the
functional IL-1 receptor, whereas the type II receptor is a decoy
receptor (9). The major IL-1 receptor found in the brain is the type I
receptor (3, 17, 47). The IL-1 type I receptor messenger RNA is also
found in the brain (11, 41, 50).
An increase in EEG SWA is usually considered an indication of increased
sleep intensity primarily because EEG SWA increases during the sleep
following sleep deprivation (5, 7). Indeed, that IL-1 enhances EEG
SWA in rats and rabbits after intracerebroventricular or intravenous
injections provides some evidence implicating IL-1 in physiological
sleep regulation. However, the effects of IL-1 on EEG SWA depend on
the route of administration and doses of IL-1. In rats
intraperitoneal injection of IL-1 (Hansen et al., unpublished
observations) induces decreases in EEG SWA and increases in duration of
NREMS; in contrast, intracerebroventricular injection of IL-1
increases both parameters. High doses of IL-1 inhibit EEG SWA in
mice (19) and rats (38). In the present study, the high dose (400 ng)
of IL-1 also decreased EEG SWA. Furthermore, Lancel and co-workers
(28) observed that NREMS is increased by IL-1 administered at the
beginning of both rest and active phases of rats, but EEG SWA is
increased by IL-1 administered at the beginning of the rest phase.
These observations suggest that the effects of IL-1 on NREMS and EEG
SWA activity can be dissociated. It is unknown how IL-1 induces
changes in EEG SWA. There are complex interactions between IL-1 and
classic neurotransmitters and humoral factors. Previously, we also
showed that IL-1 induces the release of growth hormone-releasing
hormone (GHRH), another well characterized sleep-promoting substance
that also enhances sleep and EEG SWA (35). Pretreatment of rats with
anti-GHRH antibodies inhibits IL-1-induced enhancements of NREMS and
EEG SWA (34). IL-1 also enhances the functions of 
-aminobutyric acid (GABA), an inhibitory neurotransmitter involved in sleep regulation, by increasing GABAA
receptor-mediated increases in chloride permeability in mouse cortical
synaptic preparations (31, 32). It is known that activation of
GABAA receptors results in the
suppression of EEG SWA and increases in EEG power at higher frequencies
in humans (1, 6, 8). Intraperitoneal administration of IL-1 also
increases the turnover rates of brain norepinephrine (NE) in rats (42,
48) and mice (14, 15); activation of brain NE systems is known to
suppress EEG SWA (4). It is possible that the enhancing and suppressing
effects of IL-1 on EEG SWA are mediated by different molecular
pathways.
It is well known that sleep is regulated by multiple substances
(reviewed in Ref. 25). Furthermore, the effects of a single substance
on sleep may also involve parallel and/or serial actions on
multiple molecules. It is known that IL-1 induces (22, 40) and is
induced by (2, 13) TNF-, another well-characterized sleep-promoting
substance (reviewed in Ref. 25). The present experiment showed that
TNF- induces robust increases in NREMS in IL-1RI KO mice. This
indicates that the actions of IL-1 on its type I receptor are not
required for sleep induced by TNF-. It is also unlikely that
TNF--induced sleep is mediated by IL-1 via its action on the type II
receptor, since the present results indicate that the type II receptor
is not involved in the sleep-promoting effects of IL-1. Taken
together, our results suggest that TNF- is capable of inducing sleep
without the involvement of IL-1. Previously, we also observed that
IL-1 induces sleep in TNF 55-kDa receptor knockout mice, a result
indicating that the effects of IL-1 on sleep are independent of
TNF- (19). However, these observations do not exclude the
possibility that IL-1 and TNF- may interact with each other to
promote sleep in normal animals or in other situations, such as during
infectious disease.
In summary, our results provide evidence that
1) IL-1 is involved in sleep
regulation; 2) the effects of
IL-1 on sleep are mediated by the type I receptor; and
3) TNF- is capable of inducing sleep without the involvement of IL-1.
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ACKNOWLEDGEMENTS |
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This work was supported in part by the National Institute of Neurological Disorders and Stroke (NS-25378, NS-27250, and NS-31453) and by the Office of Naval Research (N00014-90-J-1069).
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FOOTNOTES |
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Address for reprint requests: J. M. Krueger, Dept. of VCAPP, College of Veterinary Medicine, Washington State Univ., Pullman, WA 99164-6520.
Received 1 May 1997; accepted in final form 13 November 1997.
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Top
Abstract
Introduction
Methods
Results
Discussion
References
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) and interleukin-1 type I receptor knockout mice
(IL-1RI KO) (
) mice. Each data point represents a 2-h average.
Values for NREMS and REMS are expressed as % of time in each of these
states. EEG SWA data were normalized using the average of EEG SWA
during the 24-h period as 100. Vertical bars indicate SEs. Black bar at
bottom indicates dark period. Sleep and EEG SWA in both control and
IL-1RI KO mice have clear circadian rhythms. IL-1RI KO mice have
significantly less NREMS compared with controls during dark period (see
details in text).
