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Am J Physiol Regul Integr Comp Physiol 281: R1004-R1012, 2001;
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Vol. 281, Issue 3, R1004-R1012, September 2001

Interleukin-15 and interleukin-2 enhance non-REM sleep in rabbits

Takeshi Kubota1, Richard A. Brown1, Jidong Fang2, and James M. Krueger1

1 Department of Veterinary and Comparative Anatomy, Pharmacology, and Physiology, College of Veterinary Medicine, Washington State University, Pullman, Washington 99164-6520; and 2 Department of Psychiatry, Penn State College of Medicine, Hershey, Pennsylvania 17033


    ABSTRACT
TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES

Interleukin (IL)-15 and -2 share receptor- and signal-transduction pathway (Jak-STAT pathway) components. IL-2 is somnogenic in rats but has not been tested in other species. Furthermore, the effects of IL-15 on sleep have not heretofore been described. We investigated the somnogenic actions of IL-15 in rabbits and compared them with those of IL-2. Three doses of IL-15 or -2 (10, 100, and 500 ng) were injected intracerebroventriculary at the onset of the dark period. In addition, 500 ng of IL-15 and -2 were injected 3 h after the beginning of the light period. IL-15 dose dependently increased non-rapid eye movement sleep (NREMS) and induced fever. IL-15 inhibited rapid eye movement sleep (REMS) after its administration during the light period; however, all doses of IL-15 failed to affect REMS if given at dark onset. IL-2 also dose dependently increased NREMS and fever. IL-2 inhibited REMS, and this effect was observed only in the light period. IL-15 and -2 enhanced electroencephalographic (EEG) slow waves during the initial 9-h postinjection period, then, during hours 10-23 postinjection, reduced EEG slow-wave activity. Current data support the notion that the brain cytokine network is involved in the regulation of sleep.

fever; electroencephalogram; cytokine; rapid-eye movement sleep


    INTRODUCTION
TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES

IT IS WELL ESTABLISHED THAT the brain cytokine network is involved in sleep regulation. For instance, considerable evidence indicates that interleukin (IL)-1beta and tumor necrosis factor (TNF)-alpha are crucial sleep regulatory substances (SRSs) in the brain (reviewed in Refs. 26-28). These SRSs induce other SRSs, including nitric oxide (NO), PGs, growth hormone-releasing hormone (GHRH), and adenosine, thereby enhancing non-rapid eye movement sleep (NREMS; reviewed in Ref. 27).

IL-2 is a T cell growth factor and has a broad spectrum of immunoregulatory effects. IL-2 is mainly produced by helper T cells, and its production is augmented by mitogenic and antigenic stimuli. Its production is also augmented by IL-1beta (reviewed in Ref. 26). Other evidence suggests that IL-2 regulates central nervous system (CNS) functions (reviewed in Refs. 14, 37, and 42). For example, use of IL-2 for cancer immunotherapy causes CNS side effects including somnolence, depression, confusion, cognitive impairment, convulsions, and coma (9; also reviewed in Refs. 40 and 60). Systemically administered IL-2 can reach the CNS by penetrating the blood-brain barrier (BBB) or through brain areas where the BBB is absent (e.g area postrema, etc.) (reviewed in Refs. 40, 48, and 58). Furthermore, IL-2-like molecules have been detected in rodent and human brains (1, 10; also reviewed in Refs. 14 and 39). The IL-2-receptor system is present in several brain areas including the hippocampus, hypothalamus, cerebellum, frontal cortex, striatum, and locus ceruleus (reviewed in Ref. 14). Neuronal and glial cells can express IL-2 and the IL-2 receptor system (reviewed in Refs. 14, 45, 47, and 50).

IL-2 of systemic or CNS origin is thought to modulate sleep. Microinjections of IL-2 into the third ventricle or the locus ceruleus produce behavioral soporific effects as well as an increase in the lower frequency electroencephalographic (EEG) power in rats (7, 8, 41). In humans, sleep deprivation increases plasma IL-2-like activity as well as IL-1-like activity (36). Another human study showed that the production of IL-2 by stimulated mononuclear cells is increased during sleep after sleep deprivation (57). It was also reported that IL-2 production by stimulated T cells is enhanced during normal sleep in humans (4). These findings suggest a positive relationship between IL-2 and sleep regulation. However, the actions of IL-2 on rabbit sleep have not heretofore been determined. Rabbits are a standard animal model used in fever research and have been extensively used for the determination of the somnogenic actions of other cytokines (e.g., Refs. 24-29).

IL-15 has similar biological activities to those of IL-2. IL-15 and -2 are members of the four alpha -helical bundle family of cytokines. Although there is no significant sequence homology between IL-2 and -15, they share two of three receptor subunits, IL-2Rbeta and IL-2Rgamma , which are required for signaling (reviewed in Refs. 12, 23, and 59). Furthermore, the signal-transduction pathway for IL-2 and -15 is identical; both activate Janus kinase (Jak)1 and Jak3 leading to phosphorylation and nuclear translocation of the signal transducers and activators of transcription STAT3 and STAT5 (13; also reviewed in Refs. 32 and 59). This is one of the reasons for the redundancy between IL-15 and -2 functions. However, cellular sources of these cytokines are different. IL-15 mRNA is expressed in various tissues and cells, and its expression is enhanced in response to microbial products, whereas IL-2 mRNA is mainly expressed in activated T cells (reviewed in Ref. 23). Although the expression of IL-2 in the CNS is low and regionally restricted, IL-15 mRNA and its receptor subunits are constitutively present in various brain regions (13). Microglia express IL-15 and the IL-15 receptor (13). Recent human cell culture studies showed that IL-15 is expressed in astrocytes, microglia, and neuronal cell lines, and the expression is stimulated by IL-1beta , interferon (IFN)-gamma , and TNF-alpha (31, 49).

Thus we hypothesized that IL-15, similar to IL-2, could also be involved in sleep regulation. We report that intracerebroventricular (icv) injections of IL-15 and -2 enhance NREMS in rabbits.


    MATERIALS AND METHODS
TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES

Agents. Recombinant human IL-15 and -2 were purchased from R&D Systems (Minneapolis, MN). They were dissolved in pyrogen-free isotonic NaCl (PFS; Abbott Laboratories, North Chicago, IL) at concentrations of 10, 100, and 500 ng in a volume of 25 µl. 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 obtained from Western Oregon Rabbit (Philomath, OR) and surgically implanted with EEG electrodes, a brain thermistor, and a lateral icv cannula under ketamine-xylazine anesthesia as previously reported (29, 30). Briefly, the guide cannula was placed in the left lateral ventricle, 2.7-mm lateral of the bregma. A calibrated 30-kOmega thermistor (model 44008; Omega Engineering, Stamford, CT) was implanted on the dura mater over the parietal cortex to measure brain temperature (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 provided 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 (Biomedical Instrumentation, Univ. of Tennessee). The leads from the swivel and movement detectors were routed to polygraphs (Grass model 7D; Grass instrument, Quincy, MA) 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. Because of the technical problems, the number of animals from which Tbr data could be obtained was less than the number used for sleep. The vigilance states of wakefulness, NREMS, and REMS were visually determined offline in 10-s epochs by using criteria previously reported (29, 30). 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 slow-wave activity (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. Furthermore, EEG power-spectrum analyses during NREMS were performed for the 0.5- to 25-Hz frequency range. The average power in each 1-Hz frequency bandwidth during NREMS of control recordings was normalized to 100%, and then all EEG power data during the treatment-recording period were converted to a percentage of these values. The average amount of time spent in each vigilance state, EEG SWA, and Tbr were calculated for 3-h intervals. 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 (29).

Experimental protocols. In experiment I, 18 rabbits were used. They were used for different doses of IL-15. In some cases, they were used repeatedly; in those cases, at least 7 days were between cytokine injections. Furthermore, a second control baseline of sleep was determined for each rabbit to ensure that baseline values were similar to previous values from the same rabbit. Each rabbit was injected with 25 µl PFS icv on a control day. Rabbits received one of three doses of IL-15 at the onset of the dark period: 10 (n = 7), 100 (n = 8), and 500 ng (n = 10). Injections took place between 1720 and 1800. Ten rabbits received 500 ng of IL-15 at 3 h after light onset (0845-0915). Furthermore, for an additional 6 rabbits, 500 ng of heat-inactivated IL-15 (100°C, 90 min) were injected during the 40-min period preceeding dark onset. In experiment II, a different set of 18 rabbits was used. Rabbits were injected with one of three doses of IL-2 just before dark onset (1720-1800): 10 (n = 8), 100 (n = 7), and 500 ng (n = 8) on the experimental day. Eight rabbits received 500 ng of IL-2 during the light period onset (0845-0915). For an additional 8 rabbits, 500 ng of heat-inactivated IL-2 (100°C, 90 min) were injected just before dark onset. After injections, EEG, Tbr, and motor activity were recorded for the next 23 h.

Statistical analysis. Two-way ANOVA for repeated measures was used to analyze data concerning time spent of 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 or each time-block period. For power-spectrum analysis data, the EEG power density values were summed in four frequency bands [delta (0.5-4.0 Hz), theta (4.5-8.0 Hz), alpha (8.5-12.0 Hz), and beta (12.5-25.0 Hz)], and then one-way ANOVA was performed for between-group comparison. A significance level of P < 0.05 was accepted.


    RESULTS
TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES

Experiment 1: effects of IL-15 on spontaneous sleep in rabbits. The lowest dose of IL-15 (10 ng) failed to affect any of the sleep parameters measured or Tbr (Table 1 and Fig. 1). The two higher doses of IL-15 administered just before dark onset significantly increased NREMS [ANOVA for the entire 23-h period, 100 ng: time-treatment interaction F(7,49) = 2.62, P < 0.05; 500 ng: treatment effect F(1,9) = 6.05, P < 0.05 with time-treatment interaction F(7,63) = 4.00, P < 0.001; ANOVA for the 12-h dark period, 500 ng: treatment effect: F(1,9) = 5.54, P < 0.05] (Table 1 and Fig. 1). These effects were due to an increase in the number of NREMS episodes [ANOVA for the entire 23-h period, 100 ng: F(1,7) = 6.26, P < 0.05; 500 ng: F(1,9) = 14.10, P < 0.005; ANOVA for the 12-h dark period, 500 ng: F(1,9) = 9.13, P < 0.05; ANOVA for the 11-h light period, 100 ng: F(1,7) = 11.10, P < 0.05; 500 ng: F(1,9) = 8.71, P < 0.05]. IL-15 decreased the mean duration of NREMS episodes, and the effect of the 100-ng dose reached significance [ANOVA for the 23-h period: F(1,7) = 6.90, P < 0.05; ANOVA for the 11-h light period: F(1,7) = 21.40, P < 0.005; Table 2]. The 500 ng given during the light period also increased NREMS; however, it was less effective than if the same dose was given just before dark onset [ANOVA for the 23-h period: time-treatment interaction F(7,63) = 4.36, P < 0.001; ANOVA for the initial 9-h light period: treatment effect F(1,9) = 4.88, P = 0.0545, ns; Fig. 1]. REMS was inhibited after the 500-ng dose of IL-15 given during the light period [ANOVA for the 23-h period: treatment effect F(1,9) = 7.56, P < 0.05]. Although all doses of IL-15 given just before dark onset reduced REMS in the light period following the 12-h dark period, these changes did not reach significance (Table 1 and Fig. 1). EEG SWA showed a biphasic responses after the administration of IL-15 (Fig. 1). EEG SWA increased during the initial 3- to 6-h postinjection period and then decreased during the rest of the recording period [ANOVA for the 23-h period, 100 ng: time-treatment interaction F(7,49) = 2.71, P < 0.05; 500 ng: time-treatment interaction F(7,63) = 3.24, P < 0.01]. Although EEG SWA after the 500-ng dose given during the light period also showed a similar enhancement followed by a decrease, this effect was not significant. The highest dose of IL-15 significantly increased Tbr [ANOVA for the entire 23-h period, 500 ng (dark-onset administration): treatment effect F(1,6) = 6.58, P < 0.05; 500 ng (light-period administration): treatment effect F(1,9) = 8.12, P < 0.05 with time-treatment interaction F(7,63) = 3.01, P < 0.01; Table 1 and Fig. 1]. All of the effects of IL-15 were lost after heat treatment of 500 ng IL-15 (Table 1).

                              
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  		Table 1.   Effects of IL-15 and IL-2 on spontaneous sleep in rabbits



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  		Fig. 1.   Effects of intracerebroventricular (icv) injection of interleukin (IL)-15 on non-rapid eye movement sleep (NREMS), rapid eye movement sleep (REMS), electroencephalographic (EEG) slow-wave actitivy (SWA), and brain temperature (Tbr) in rabbits. Open circles and closed circles represent pyrogen free saline (PFS) and IL-15 treatment, respectively. Horizontal shaded bars denote dark phase of the day. The average power of EEG SWA throughout the entire 23-h control-recording period was normalized to 100% for each animal. Then, all SWA data were converted to a percentage of the control values. Data are means ± SE.


                              
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  		Table 2.   Effects of IL-15 and IL-2 on NREMS cycles

Experiment 2: effects of IL-2 on spontaneous sleep in rabbits. IL-2 dose dependently increased NREMS, and significant effects were observed after all doses [ANOVA for the entire 23-h period, 10 ng: time-treatment interaction F(7,49) = 3.00 P < 0.05; 100 ng: treatment effect F(1,6) = 6.84, P < 0.05 with time-treatment interaction F(7,42) = 3.41, P < 0.01; 500 ng: treatment effect F(1,7) = 7.91, P < 0.05 with time-treatment interaction F(7,49) = 4.65, P < 0.0005; ANOVA for the 12-h dark period, 100 ng: treatment effect F(1,6) = 7.70, P < 0.05; 500 ng: treatment effect F(1,7) = 9.22, P < 0.05; Table 1 and Fig. 2]. These effects were mainly due to an increase in the number of NREMS episodes, although at some doses, these changes did not reach significance (Table 2). IL-2 given during the light period also markedly enhanced NREMS with an increase in the number of NREMS episodes [ANOVA for 23 h; treatment effect F(1,7) = 16.44, P < 0.005 with time-treatment interaction F(7,49) = 4.36, P < 0.0005; ANOVA for the initial 9-h light period: treatment effect F(1,7) = 20.86, P < 0.005; ANOVA for the number of the NREMS episodes for 23 h: F(1,7) = 9.04, P < 0.05; for the initial 9 h: F(1,7) = 6.45, P < 0.05; for the 12-h dark period: F(1,7) = 7.69, P < 0.05]. REMS was significantly inhibited only in the light period [ANOVA for the entire 23-h period, 10 ng: time-treatment interaction F(7,49) = 2.54, P < 0.05; 100 ng: time-treatment interaction F(7,42) = 3.59, P < 0.005; ANOVA for the 11-h light period; 100 ng: treatment effect F(1,6) = 7.89, P < 0.05; Table 1 and Fig. 2]. The inhibition of REMS was due to a decrease in the number of REMS episodes [ANOVA for the 23-h period, 100 ng: F(1,6) = 12.40, P < 0.05; ANOVA for the 11-h light period, 100 ng: F(1,6) = 30.00, P < 0.005] (Table 3). The inhibitory effect of REMS during the light period after the highest dose given at dark onset approached but failed to reach significance [ANOVA for 11-h light period: treatment effect F(1,7) = 5.39, P = 0.0533]. REMS was also decreased in the light period after the 500 ng of IL-2 given during the light period [ANOVA for the 23-h recording period: time-treatment interaction F(7,49) = 2.81, P < 0.05; ANOVA for the 9-h light period: treatment effect F(1,7) = 5.61, P < 0.05]. This effect was also due to a decrease in the number of REMS episodes [ANOVA for the 23 h: F(1,7) = 6.77, P < 0.05]. EEG SWA had a biphasic pattern after IL-2 treatment (Fig. 2). It was increased during the initial 9 h postinjection and then decreased during the rest of recording period. This effect was found even after the lowest dose, and significant time-treatment interactions were observed [ANOVA, time-treatment interaction for the entire 23-h period, 10 ng: F(7,49) = 4.54, P < 0.001; 100 ng: F(7,42) = 3.25, P < 0.01; 500 ng (dark-onset administration): F(7,49) = 8.03, P < 0.0001; 500 ng (light-period administration): F(7,49) = 7.04, P < 0.0001].


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  		Fig. 2.   Effect of icv injection of IL-2 on NREMS, REMS, EEG SWA, and Tbr in rabbits. Open circles and closed circles represent PFS and IL-15 treatment, respectively. Data are means ± SE.


                              
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  		Table 3.   Effects of IL-15 and IL-2 on REMS cycles

IL-2 was also pyrogenic (Fig. 2). It significantly increased Tbr after all doses [ANOVA for 23 h, 10 ng: treatment effect F(1,6) = 6.57, P < 0.05 with time-treatment interaction F(7,42) = 2.67, P < 0.05; 100 ng: treatment effect F(1,6) = 12.01, P < 0.05; 500 ng (dark-onset administration): treatment effect F(1,6) = 7.98, P < 0.05 with time-treatment interaction F(7,49) = 3.83, P < 0.005; 500 ng (light-period administration): treatment effect F(1,7) = 21.64, P < 0.005 with time-treatment interaction F(7,49) = 2.72, P < 0.05]. All the IL-2-induced effects were lost after the heat inactivation of 500 ng IL-2 (Table 1).

Effects of IL-15 and -2 on the EEG power spectrum. After the 500-ng doses of IL-15 and -2 given just before dark onset, there was an enhancement of EEG power in the frequencies below 5 Hz (Fig. 3). In contrast to the effects observed during the initial 6 h after dark onset (12 h after cytokine treatment), both IL-15 and -2 decreased power in the low-frequency bands (<15 Hz) during the first 6 h after light onset (Fig. 3). The effect of IL-2 on the delta power during the initial 6-h administration was higher than that of IL-15, although the difference between these effects did not reach significance [ANOVA; F(1,16) = 2.60, P = 0.1262].


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  		Fig. 3.   EEG power spectrum analysis during NREMS obtained after either IL-2 or -15 administration just before dark onset. The %change in power density of each frequency band from the time- and sleep state-matched values during the control recordings is shown. Left: data obtained during the first 6 h postinjection. Right: data from the same animals taken between 12-18 h postinjection (i.e., during the first 6 h of the light period). Open circles and closed circles represent 500 ng of IL-15 and -2 treatment, respectively. IL-15 and -2 induced similar effects on the EEG during NREMS.


    DISCUSSION
TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES

The major finding of the present study is that IL-15 and -2 enhance NREMS in rabbits. Our current results are consistent with the previous reports of IL-2 somnogenic activity in rats. De Sarro and colleagues (7, 8) showed that microinjection of IL-2 into the third ventricle or locus coeruleus induced sleep responses in rats. The mechanisms by which IL-2 induce sleep remain unknown, although several are proposed. For instance, De Sarro and colleagues demonstrated that the somnogenic actions of IL-2 were antagonized by pretreament with naloxone, an opioid-receptor antagonist. Thus they concluded that opiate and IL-2 receptors might be functionally coupled. Another possible mechanism is that IL-2 elicits sleep by inducing production of other SRSs. Weil and Dautry (62) reported that IL-2 induces the expression of TNF-alpha , TNF-beta , and IFN-gamma in murine lymphoid cell lines. Lu and co-workers (33) reported that IL-2 promotes TNF-beta transcription via the Jak-STAT pathway, and STAT proteins seem to be involved in TNF-alpha gene expression (5). TNF-alpha and -beta enhance NREMS in several species (11, 19, 21, 53). Furthermore, we recently found that IFN-gamma also has hypnotic actions in rabbits and mice (unpublished data). Moreover, IL-2 activates neural NO synthase (NOS) via the stimulation of cholinergic neurons (22). NO is thought to be an important SRS (e.g., Refs. 18 and 20). Although the interactions of IL-15 with other SRSs are unclear, similar mechanisms are likely to be involved because they share several components of the signaling pathway including Jak1, Jak3, STAT3, and STAT5 (reviewed in Refs. 32, 54, and 59) .

Current results suggest that the Jak-STAT pathway may be involved in sleep regulation. This hypothesis is also supported by the findings that other somnogenic substances including IFNs (24) and IL-3 (7, 41) also activate the Jak-STAT pathway (reviewed in Ref. 16). Furthermore, a recent report suggests a synergistic interaction of nuclear factor kappa B (NF-kappa B) and the STAT pathway. Sekine et al. (52) reported that IFN-gamma -induced activation of STAT1 potentiates TNF-alpha -induced NF-kappa B activation. Previously, NFkappa B was implicated in the regulation of SRSs (3, 6, 15, 27, 30, 38; and reviewed Refs. 44, 46, 55).

In the present study, both of IL-15 and -2 had a biphasic effect on EEG SWA. This effect is also observed after IL-1beta (30). Thus an icv injection of 10 ng IL-1beta significantly increased EEG SWA during the initial 6-h postinjection period and then significantly decreased EEG SWA for the remainder of the recording period in rabbits (30). The mechanism for cytokine-induced enhancement of EEG SWA is still obscure; however, the mechanism of IL-1 enhanced EEG SWA is possibly different from that of IL-2. IL-1 is thought to modulate gamma -aminobutyric acid (GABA) in the brain; GABAergic mechanisms are involved in the generation of EEG slow waves. Thus Miller et al. (35) demonstrated that IL-1 enhances a GABA-mediated increase in chloride permeability in cortical synaptosomes. Furthermore, they also demonstrated that IL-1 potentiates GABA-mediated inward currents in cultured cortical neurons (34, 35). These effects were IL-1 specific and not observed after the IL-6 or TNF treatment. Another group reported that microinjection of IL-2 into the third ventricle or the locus ceruleus induces EEG synchronization and an increase in EEG power in low-frequency bands. These effects were antagonized by naloxone. IL-1 elicited similar responses as did IL-2; however, this effect was not antagonized by naloxone (7, 8, 41). Many opioids induce EEG high-amplitude delta waves (51). For instance, a microinjection of dermorphin, a µ-opioid-receptor agonist, into the locus ceruleus dose dependently produces EEG synchronization with a significant increase in the EEG power in low-frequency bands (2). Therefore, it is possible that IL-2 increases EEG SWA via stimulation of opioid receptors.

High doses of both of IL-15 and -2 inhibit REMS while simultaneously enhancing NREMS. High NREMS-promoting doses of IL-1 (30, 43, 53, 61), TNF-alpha (19, 53), TNF-beta (21), and IFN-alpha (25) induce similar responses. Similar sleep patterns characterized by an increase in NREMS and a decrease in REMS are observed during the acute phase response after infectious challenge (56), and it is likely that IL-15 and -2, as well as these other cytokines, are involved in the sleep responses during infection. Interestingly, IL-15- and IL-2-induced REMS inhibitions are phase dependent. Other inflammatory cytokines such as IL-1beta (30) and -18 (unpublished data) also induce a phase-dependent inhibition of REMS, and these effects are observed only in the light phase. The failure of these cytokines to inhibit REMS during the dark phase may be a consequence of the low levels of REMS that normally occur in the dark phase. Alternatively, these findings could imply that the neurohumoral factors that regulate the circadian rhythm are involved in the mechanisms of REMS suppression, a notion consistent with the two-process model of sleep regulation. Possibly, IL-2 affects the neurotransmitter systems that are associated with REMS regulation. Much evidence shows that IL-2 modulates brain cholinergic, noradrenergic, and dopaminergic systems (reviewed in Ref. 14).

Central administration of IL-15 and IL-2 markedly increase Tbr in rabbits, and this action is lost after heat treatment. In rats, IL-2 injection did not affect body temperature (7). This discrepancy is likely due to a species differences. The mechanisms of pyrogenic action of these cytokines are unknown. However, it is possible that these cytokines may induce other pyrogenic cytokines such as TNF-alpha and -beta via the Jak-STAT pathway (5, 33). TNF activates NF-kappa B transcription and thereby induces cyclooxygenase-2 (17). As a result, it would likely enhance the production of endogenous pyrogens like PGs.

In conclusion, IL-15 and IL-2 have the capacity to enhance NREMS. Although it is still unclear whether these cytokines are involved in the regulation of physiological sleep and/or sleep responses during infection, the data in the present study support the hypothesis that a cytokine network in the brain regulates sleep. Furthermore, our current results suggest the hypothesis that the Jak-STAT pathway is also involved in the regulation of sleep.


    ACKNOWLEDGEMENTS

This work was supported by grants from the National Institutes of Health (NS-25378, NS-31453, and HD-36520).


    FOOTNOTES

Address for reprint requests and other correspondence: J. M. Krueger, Dept. of VCAPP, Washington State Univ.; 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. Section 1734 solely to indicate this fact.

Received 21 December 2000; accepted in final form 10 May 2001.


    REFERENCES
TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES

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Am J Physiol Regul Integr Comp Physiol 281(3):R1004-R1012
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