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1 inhibit
spontaneous sleep in rabbits
Washington State University, College of Veterinary Medicine, Department of Veterinary and Comparative Anatomy, Pharmacology and Physiology, Pullman, Washington 99164
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ABSTRACT |
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 TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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Proinflammatory cytokines,
including interleukin-1
and tumor necrosis factor-
are involved
in physiological sleep regulation. Interleukin (IL)-13 and transforming
growth factor (TGF)-1 are anti-inflammatory cytokines that inhibit
proinflammatory cytokines by several mechanisms. Therefore, we
hypothesized that IL-13 and TGF-1 could attenuate sleep in rabbits.
Three doses of IL-13 (8, 40, and 200 ng) and TGF-1 (40, 100, and 200 ng) were injected intracerebroventricularly 3 h after the
beginning of the light period. In addition, one dose of IL-13 (200 ng)
and one dose of TGF-1 (200 ng) were injected at dark onset. The two
higher doses of IL-13 and the highest dose of TGF-1 significantly
inhibited spontanenous non-rapid eye movement sleep (NREMS) when they
were given in the light period. IL-13 also inhibited NREMS after dark onset administration; however, the inhibitory effect was less potent
than that observed after light period administration. The 40-ng dose of
IL-13 inhibited REMS duration during the dark period. TGF-1
administered at dark onset had no effect on sleep. These data provide
additional evidence for the hypothesis that a brain cytokine network is
involved in regulation of physiological sleep.
non-rapid eye movement sleep; electroencephalogram; cytokine; brain
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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SLEEP IS REGULATED,
in part, by humoral mechanisms. The proinflammatory cytokines
such as interleukin (IL)-1 and tumor necrosis factor (TNF)- are
involved in physiological sleep regulation (reviewed in Ref. 23).
Administration of IL-1 (13, 35, 46) or TNF- (14, 19,
46) increases non-rapid eye movement sleep (NREMS), and
inhibition of IL-1 (18, 38,
39, 51) or TNF- (50,
52-54, 56) inhibits NREMS in a variety
of species. IL-4, IL-10, IL-13, and transforming growth factor
(TGF)-1 are classified as anti-inflammatory cytokines (reviewed in
Refs. 21 and 22). Previously, we showed that IL-4 (27) and
IL-10 (26) inhibit NREMS in rabbits after
intracerebroventricular administration. Moreover, IL-10 inhibits NREMS
in rats (40). However, the effects of IL-13 and TGF-1
on sleep have not yet been reported.
IL-13 is considered to be an important macrophage-deactivating factor.
IL-13 shares many of its biological functions with IL-4. They have a
20-25% homology in their amino acid structure. Moreover, IL-13
and IL-4 receptors involve a common component, IL-4R (reviewed in
3). IL-13 suppresses IL-1 and TNF- production in vitro
(5, 9, 61). Some in vivo studies
also demonstrate that IL-13 inhibits LPS-induced TNF- and IL-1
production in mice (10, 34). Moreover, IL-13
promotes the production of additional anti-inflammatory substances
including the IL-1 receptor antagonist (9,
33, 59, 61) and the IL-1 type II
receptor (4).
TGF-1 is an important regulator of immune and inflammatory processes
in the central nervous system (CNS) (reviewed in Ref. 30). TGF-1 is
part of a complex network that forms a negative-feedback system for
IL-1 and TNF- production (43). IL-1 stimulates TGF-1 expression in glial cells (7). Conversely, TGF-1
suppresses microglial activation, proliferation, and IL-1 and
TNF- production (47). TGF-1 also inhibits
IL-1-induced cellular inflammation in the retina (6).
Furthermore, TGF- receptor mRNAs and proteins are present in the CNS
(60).
These findings suggest that IL-13 and TGF-1 could modulate
endogenous sleep regulatory substances and, thereby, affect sleep. We
report here that IL-13 and TGF-1 inhibit rabbit NREMS without affecting brain temperature (Tbr) and electroencephalographic (EEG)
slow-wave activity (SWA).
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MATERIALS AND METHODS |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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Agents.
Recombinant human IL-13 and TGF-1 were purchased from R&D Systems
(Minneapolis, MN). IL-13 was dissolved in pyrogen-free isotonic NaCl
(PFS; Abbott Laboratories, North Chicago, IL) at the concentrations of
8, 40, and 200 ng in volumes of 25 µl. TGF-1 was dissolved in 25 µl PFS at the doses of 40, 100, and 200 ng. They were stored under
sterile conditions at 
80°C until the experiment.
Animals.
Male New Zealand White Pasteurella-free rabbits weighing 3.5-4.5
kg were surgically implanted with EEG electrodes, a brain thermistor,
and a lateral intracerebroventricular cannula under ketamine-xylazine
anesthesia as previously described (26, 27). Briefly, the guide cannula was placed in the left lateral ventricle for
intracerebroventricular injection. A calibrated 30-k
thermistor (model 44008; Omega Engineering, Stamford, CT) was implanted on the
dura mater over the parietal cortex to measure Tbr. The leads from the
electrodes and the thermistor were routed to a Teflon pedestal. The
pedestal, guide cannula, and leads were attached to the skull with
dental acrylic (Duz-All; Coralite Dental Products, Skokie, IL). After
at least 2 wk of recovery, the animals were placed in experimental
chambers (Hot Pack 352600, Philadelphia, PA). The animals were kept on
a 12:12-h light-dark cycle (0600 light on) at 21 ± 1°C ambient
temperature. Water and food were ad libitum throughout the experiment.
Recording and analysis.
A flexible tether connecting the EEG electrodes and the thermistor was
led to an electronic swivel (SL6C, Plastics One, Roanoke, VA). Body
movements were detected by ultrasonic detectors (Biochemical Instrumentation, University of Tennessee). The leads from the swivel
and movement detectors were routed to Grass model 7D polygraphs in an
adjacent room. The EEG was filtered below 0.1 Hz and above 35 Hz. The
amplified signals were digitized at the frequency of 128 Hz for the EEG
and at 2 Hz for Tbr and motor activity. Tbr data were saved on a
computer in 10-s intervals. The vigilance states of wakefulness, NREMS
and rapid eye movement sleep (REMS) were visually determined offline in
10-s epochs by using criteria previously reported (26,
27). In brief, wakefulness was characterized by fast
low-amplitude EEG waves, gradually increasing Tbr, and a high incidence
of gross body movements. NREMS was associated with slow high-amplitude
EEG waves, slowly decreasing Tbr, and lack of body movements. In
contrast, REMS was characterized by fast low-amplitude EEG waves,
appearance of theta activity in the EEG, rapidly increasing Tbr at REMS
onset, and a lack of body movement. Online Fourier analysis of the EEG
was performed. The average of EEG power density in the delta frequency
band (0.5-4.0 Hz) during NREMS, also called EEG SWA, was
calculated. The average power of EEG SWA throughout the entire 23-h
control recording period was normalized to 100% for each animal. Then
all EEG SWA data were expressed as a percentage of that control value.
The average amount of time spent in each vigilance state, EEG SWA, and
Tbr were calculated for 2-h intervals for purposes of graphic display
(Figs. 1 and
2). In addition, the number of NREMS and REMS episodes, the mean episode length, and mean length of sleep cycles
(R-R interval: time between the onset of a REMS episode and the onset
of the next REMS episode) were determined using a computer program with
the criterion that each REMS episode lasted at least 30 s.
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Experimental protocols.
Each rabbit was injected with 25 µl PFS intracerebroventricularly on
a separate control day. If a rabbit was used more than once, at least 7 days separated the injections, and a separate control day recording was
obtained. In experiment 1, 12 rabbits were used. Rabbits
received one to three doses of IL-13 during the light period: 8 (n = 7), 40 (n = 8), and 200 ng
(n = 8). Injections took place between 0845 and 0915. Eight rabbits received 200 ng of IL-13 at dark onset
(1800). In experiment 2, a different set of 12 rabbits was used. Rabbits were injected with one to three doses of
TGF-1 during light period (0845-0915): 40 (n = 8), 100 (n = 7), and 200 ng
(n = 8) on the experimental day. Nine rabbits received
200 ng of TGF-1 at dark onset (1800). After injections, EEG, Tbr, and motor activity were recorded for the next 23 h.
Statistical analysis. Two-way ANOVA for repeated measures followed by a Student-Newman-Keuls test was used to analyze data concerning time spent at each vigilance state, EEG SWA, and Tbr; 3-h time blocks were used for these analyses. For the sleep-episode data, one-way ANOVA for repeated measures was used for the entire 23-h period, the 9-h light period between the time of injection and the dark period, and the 12-h dark period. A significance level of P < 0.05 was accepted.
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RESULTS |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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Experiment 1: effects of IL-13 on spontaneous sleep in rabbits.
The lowest dose of IL-13, 8 ng, failed to affect any of the sleep
parameters measured (Table 1). In
contrast, the two higher doses of IL-13 administered during the light
period significantly inhibited NREMS [ANOVA treatment effects for the
entire 23-h postinjection period: 40 ng,
F(1,7) = 15.79, P = 0.0054; 200 ng,
F(1,7) = 7.04, P = 0.0325; ANOVA treatment effects for the 12-h dark
period: 40 ng, F(1,7) = 11.61, P = 0.0113; 200 ng,
F(1,7) = 7.28, P = 0.0307; Table 1 and Fig. 1]. The NREMS inhibitory
effect during the dark period was due to a decrease in the number of
NREMS episodes [ANOVA for the 12-h dark period: 200 ng,
F(1,7) = 9.70, P = 0.0170; Table 2].
The decreases in NREMS during the initial 9-h light period did not
reach significance after any dose. The 200-ng dose given at dark onset
also inhibited NREMS; however, it was less effective than the same dose
given during the light period [ANOVA treatment effects for the 23-h
postinjection period: F(1,7) = 17.36, P = 0.0042; Table 1 and Fig. 1]. This effect
was also due to a decrease in the number of NREMS episodes [ANOVA for
23 h: F(1,7) = 6.35, P = 0.0398; Table 2]. REMS was inhibited during the
dark period after the 40-ng dose of IL-13 [ANOVA for the 12-h dark
period: F(1,7) = 9.94, P = 0.0161], and it was due to a decrease in the
number of REMS episodes [ANOVA for 12 h:
F(1,7) = 13.5, P = 0.0080]. As a result, a significant increase in
the sleep-cycle length (R-R interval) was observed [ANOVA for 23 h: F(1,7) = 5.80, P = 0.0469; Tables 1 and
3]. Although a significant decrease in
the total amount of time in REMS was not found after 200 ng of IL-13
administration at dark onset, the number of REMS episodes during the
dark period was significantly inhibited [ANOVA for the 12-h dark
period: F(1,7) = 9.21, P = 0.0188; Table 3]. EEG SWA and Tbr were not
affected by any of the IL-13 doses tested. Furthermore, IL-13 did not
induce gross abnormal behavior; animals appeared normal when handled,
and no motor abnormalities were evident.
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Experiment 2: effects of TGF-1 on spontaneous sleep in rabbits.
The lowest dose of TGF-1 did not affect any of the sleep
parameters measured. The middle dose of TGF-1 decreased the amount of time spent in NREMS, but this effect did not reach significance [ANOVA treatment effect for the 23-h postinjection period:
F(1,6) = 4.84, P = 0.0701]. The highest dose of TGF-1
significantly decreased time spent in NREMS [ANOVA treatment effect
for 23 h: F(1,7) = 15.58, P = 0.0056; for the initial 9 h:
F(1,7) = 9.84, P = 0.0164], and it was due to a decrease in the
duration of NREMS episodes [ANOVA for 23 h:
F(1,7) = 11.20, P = 0.0122; for the initial 9 h:
F(1,7) = 10.50, P = 0.0141; Tables 1 and 2]. The 200-ng dose given at
dark onset inhibited NREMS in the light period; however, this effect
did not reach significance [ANOVA treatment effect for the 11-h light
period: F(1,8) = 4.20, P = 0.0744; Table 1]. REMS, EEG SWA, and Tbr were not
affected by any of the TGF-1 doses given. Furthermore, abnormal
behavior was not observed after any dose of TGF-1.
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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The major finding in the present study is that both IL-13
and TGF-1 inhibit NREMS. These effects are similar to those we previously reported for IL-4 and IL-10 (26,
27). These inhibitory actions are likely due to inhibition
of production of endogenous sleep regulatory substances such as
IL-1, TNF-, and nitric oxide (NO). IL-13 (5,
9, 10, 34, 61) and
TGF-1 (47) suppress IL-1 and TNF- production.
They inhibit the expression of the inducible NO synthase, a
rate-limiting enzyme for the production of NO (1,
31). IL-4 (1, 20,
29, 32) and IL-10 (12, 15, 28, 57) also have these properties.
The present study also shows that injections of IL-13 and TGF-1 at
dark onset are less effective than injections in the light period. We
also reported that IL-4 and IL-10 had no inhibitory effects after
dark-onset administration (26, 27). Normally, IL-1 mRNA and TNF- mRNA levels are lowest at dark onset, hence their productions at that time are likely low (17,
48). Therefore, it is possible that the inhibitory effects
of IL-13 or TGF-1 on IL-1 and TNF- production may be less
potent during the dark period. The onset of inhibitory effects on NREMS
induced by IL-13 and TGF-1 is shorter than that observed in IL-4 and
IL-10. The sleep-inhibitory effects of IL-4 and IL-10 are not
manifested until 8-10 h after their administration
(26, 27). There are several possibilities for
this difference. For example, it is possible that the times for
diffusion of these inhibitory cytokines to effective sites can be
different, because the location of these sites are still obscure. As
another possibility, it may due to the stimulation of production of
sleep-inhibitory substances such as receptor antagonists or soluble
receptors for IL-1 and TNF- by inhibitory cytokines.
Administration of substances that bind IL-1 or TNF rapidly, such as
antibodies and soluble receptors for IL-1 (36,
51) and TNF- (50, 52,
53, 57), inhibit NREMS within the first
postinjection hour. Thus, if the ability of IL-13 or TGF-1 to induce
production of these inhibitory substances is relatively rapid, then the
latency for NREMS inhibitory effects could be shorter. Although the
time course for this effect is unclear, IL-13 promotes the production
of the IL-1 type II receptor, a decoy receptor (4), as
well as the IL-1 receptor antagonist (9, 33,
59, 61). TGF- can also antagonize the
effects of IL-1 by increasing the expression of the IL-1 receptor
antagonist (58) as well as decreasing cell surface
expression of IL-1 receptors (11, 44). It is
likely that the NREMS inhibitory effects of IL-13 and TGF-1 result
from one or more of these mechanisms.
Although the present study did not show clear dose-dependent inhibition
of REMS, IL-13 slightly inhibited REMS. It is thought that
sleep-regulatory mechanisms of REMS are different from those of NREMS.
In cats, microinjection of NO synthase inhibitors into the
pedunculopontine tegmental area reduces REMS as well as NREMS (8). Therefore, brain stem NO ergic mechanisms could be
implicated in the inhibitory effect of REMS by IL-13. Although we did
not show any inhibitory effect for REMS by TGF-1, it is possible that the doses used in this study were insufficient to reveal a
REMS-inhibitory effect; as mentioned above, TGF-1 also inhibits NO
production. We previously reported that IL-4 and IL-10 inhibited REMS
only in the highest doses used (26, 27).
These results suggest that the doses of inhibitory cytokines required
for REMS inhibition are higher than those needed for NREMS inhibition.
In the present study, neither IL-13 nor TGF-1 affected EEG SWA.
Previously, we reported that IL-4 and IL-10 also did not affect EEG SWA
(26, 27). Therefore, we can conclude that
those anti-inflammatory cytokines tested thus far do not change EEG SWA
in the doses that reduce NREMS. EEG SWA reflects the intensity of NREMS
under many conditions (41). For example, EEG SWA is markedly increased during the deep sleep occurring after sleep deprivation (42). IL-1 and TNF- are involved in this
effect because sleep deprivation-enhanced EEG SWA is attenuated if
animals are pretreated with inhibitors if IL-1 or TNF (37,
49, 53). The reason why IL-4, IL-10, IL-13,
or TGF-1 does not inhibit spontaneous EEG SWA remains unclear.
However, the mechanisms responsible for EEG SWA are different from
those responsible for NREMS, and thus it is reasonable to expect that
these parameters can vary independently in some experimental
conditions. For example, neurotrophin 1 and 2 promote NREMS but
slightly decrease EEG SWA (25, 55). Benzodiazepine hypnotics promote NREMS with decreases in EEG SWA. A
benzodiazepine-receptor antagonist antagonizes drug-induced NREMS but
does not antagonize the effect on EEG SWA (reviewed in Ref. 2). The
diurnal rhythms of NREMS in rats allowed food intake only during
daylight hour shifts to one characterized by more NREMS during the dark
than during the day; the rhythms of EEG SWA are not changed by
restricted food intake (45). Furthermore, it is also
possible that the mechanisms responsible for duration of NREMS and EEG
SWA may have different thresholds for the inhibitory effects of IL-13
and TGF-1.
IL-13 and TGF-1 failed to affect Tbr. These data are also consistent
with those obtained after IL-4 and IL-10 treatment (26, 27). Tbr is coupled to sleep states, but there are many
conditions in which they are not tightly linked. For example,
antipyretics antagonize IL-1-induced fever, but not sleep responses. In
contrast, inhibitors of NO synthase block IL-1-induced sleep
response, but not fevers (reviewed in Ref. 24). The lack of effect of IL-13 and TGF-1 on Tbr at the doses that inhibit NREMS suggests that
proinflammatory cytokines may have little effect in the regulation of
normal body temperature.
The physiological functions of IL-13 in peripheral tissue have been
studied; however, the function of IL-13 in the CNS has not yet been
elucidated. TGF-1 is involved in cell growth, differentiation, adhesion, and proliferation in the CNS; however, it is expressed mainly
in pathological conditions during adulthood (reviewed in Ref. 16).
Therefore, we cannot conclude that these cytokines are involved in
physiological sleep regulation. However, current data support the
hypothesis that the cytokine network in the brain plays an important
role in physiological sleep regulation.
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ACKNOWLEDGEMENTS |
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We thank Richard A. Brown for expertise in animal care.
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FOOTNOTES |
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This work was supported, in part, by grants from the National Institutes of Health (NS-25378, NS-31453, and HD-36520).
Address for reprint requests and other correspondence: J. M. Krueger, P.O. BOX 646520, Pullman, WA 99164-6520 (E-mail: krueger{at}vetmed.wsu.edu).
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.
Received 2 February 2000; accepted in final form 27 March 2000.
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REFERENCES |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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, Vehicle
treatment group; 
, IL-13 treatment group. Horizontal shaded bars
denote dark phase. IL-13 (200 ng) was injected either during the light
phase (A) or at dark onset (B). IL-13
significantly inhibited NREMS. All data shown are averages obtained
from 2-h intervals and expressed as means ± SE.
