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Am J Physiol Regul Integr Comp Physiol 281: R828-R838, 2001;
0363-6119/01 $5.00
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Vol. 281, Issue 3, R828-R838, September 2001

Interleukin-18 promotes sleep in rabbits and rats

Takeshi Kubota, Jidong Fang, Richard A. Brown, and James M. Krueger

Department of Veterinary and Comparative Anatomy, Pharmacology and Physiology, Washington State University, Pullman, Washington 99164 - 6520


    ABSTRACT
TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES

Interleukin (IL)-1beta is involved in physiological sleep regulation. IL-18 is a member of the IL-1 family, and its signal-transduction mechanism is similar to that of IL-1. Therefore, we hypothesized that IL-18 might also be involved in sleep regulation. Three doses of IL-18 (10, 100, and 500 ng) were injected intracerebroventricularly (icv) into rabbits at the onset of the dark period. The two higher doses of IL-18 markedly increased non-rapid eye movement sleep (NREMS), accompanied by increases in brain temperature (Tbr). These effects were lost after the heat inactivation of IL-18. The 500 ng of IL-18 injection during the light period also increased NREMS and Tbr. Similar results were obtained after icv injection of 100 ng of IL-18 into rats. Furthermore, intraperitoneal injection of 30 µg/kg of IL-18 slightly, but significantly, increased NREMS, whereas it significantly decreased electroencephalogram slow-wave activity in rats. Intraperitoneal IL-18 failed to induce fever. An anti-human IL-18 antibody had little effect on spontaneous sleep in rabbits, although the anti-IL-18 antibody significantly attenuated muramyl dipeptide-induced sleep. These data suggest that IL-18 is involved in mechanisms of sleep responses to infection.

electroencephalogram; cytokine; muramyl dipeptide


    INTRODUCTION
TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES

SLEEP IS REGULATED BY HUMORAL MECHANISMS, including the brain cytokine network. For instance, central or systemic administration of interleukin (IL)-1beta or tumor necrosis factor (TNF)-alpha increases non-rapid eye movement sleep (NREMS) in several species (25, and reviewed in Refs. 20 and 22). In contrast, inhibition of IL-1beta or TNF-alpha using the IL-1-receptor antagonist (36), IL-1, or TNF-receptor fragments (52, 54, 55), soluble IL-1 or TNF receptors (18, 55), or antibodies to IL-1 or TNF (37, 38, 50) inhibits spontaneous NREMS in rats and rabbits. These well-characterized sleep-regulatory substances activate the transcription factor nuclear factor kappa B (NF-kappa B) (reviewed in Refs. 2 and 35). NF-kappa B promotes production of many substances implicated in sleep regulation [e.g., nitric oxide synthase (NOS), cyclooxygenase-2 (COX-2), nerve growth factor, the adenosine A1 receptor, IL-2, IL-1, and TNF]. IL-1 and TNF are also involved in the sleep responses occurring during infection (reviewed in Ref. 19). Sleep responses elicited by microbial challenge are a facet of the acute phase response, and they likely provide a beneficial aid for recuperation (58). However, our current knowledge of the biochemical mechanisms responsible for these sleep responses is very limited (reviewed in Ref. 19).

IL-18 is a relatively newly characterized cytokine also involved in host defenses (reviewed in Refs. 7 and 8), which was first described in 1989 as an endotoxin-induced serum factor that stimulates interferon (IFN)-gamma production (32); the same group subsequently isolated IL-18 (31). There are many similarities between IL-18 and IL-1. IL-18 includes IL-1 signature-like sequences. The amino acid sequence homologies between human IL-18 and IL-1beta , IL-1alpha , and the IL-1 receptor antagonist are between 15% and 18% (59). Furthermore, the biologically inactive precursors of IL-1beta and IL-18 are cleaved by an IL-1beta -converting enzyme (ICE) and thereby become the active forms (12). Moreover, a component of the functional IL-18-receptor complex is the IL-1-receptor-related protein (57). Another important part of the IL-18-receptor complex is an accessory protein that is related to the IL-1-receptor accessory protein (reviewed in Refs. 7 and 8).

IL-18 is expressed constitutively in rat brain, including the cerebellum, hippocampus, hypothalamus, cortex, and striatum (6). IL-18 mRNA is present in cultures of astrocytes and microglia but not in neurons. ICE is present at constitutive levels in microglia and astrocytes, suggesting that these cell types produce mature IL-18 (5). IL-18 stimulates TNF-alpha production. IL-18 also induces IL-1beta via TNF-alpha production (45). Furthermore, IL-18 activates NF-kappa B (29, 47). Collectively, these findings suggest that IL-18 could be involved in sleep regulation as well as the sleep responses to infection. We report here that IL-18 enhances NREMS and brain temperature (Tbr) in rabbits and rats. Furthermore, immunoneutralization of anti-IL-18 attenuated N-acetylmuramyl-L-alanyl-D-isoglutamine [(MDP) a substance derived from bacterial peptidoglycan (43)]-induced sleep, thereby suggesting that IL-18 is involved in sleep responses associated with microbial challenge.


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

Agents

Recombinant human IL-18 and rat IL-18 were purchased from R&D systems (Minneapolis, MN). Murine IL-18 was purchased from Peprotech (Rocky Hill, NJ). Human IL-18 and murine IL-18 were given intracerebroventricularly (icv) to rabbits and rats, respectively. They were dissolved in pyrogen-free isotonic saline (PFS; Abbott Laboratories, North Chicago, IL) at concentrations of 10, 100, and 500 ng in a volume of 25 µl (for rabbits) and 1, 10, and 100 ng in a volume of 2.5 µl (for rats). For intraperitoneal (ip) injections of rats, rat IL-18 was given. It was dissolved at concentrations of 0.3, 3, and 30 µg in a volume of 100 µl. IL-18 samples were stored under sterile conditions at -80°C until the experiment. For experiments IV and V (see below), anti-human IL-18 monoclonal antibody and normal mouse IgG2A were purchased from R&D systems. They were dissolved in PFS at concentrations of 2.5 and 25 µg/25 µl in experiment IV and 25 µg/15 µl in experiment V. MDP was purchased from Sigma (St. Louis, MO). It was dissolved in PFS at concentrations of 25, 75, and 150 pmol/10 µl.

Animals

Male New Zealand White Pasteurella-free rabbits (3.5-4.0 kg) and Sprague-Dawley rats (280-350 g) were surgically implanted with electroencephalogram (EEG) electrodes, a brain thermistor, a lateral icv cannula, and an electromyogram (EMG) electrode (only for rats) as previously described (27). Briefly, stereotaxic surgery was performed under ketamine-xylazine (35 and 5 mg/kg for rabbits; 87 and 13 mg/kg for rats) anesthesia. A lateral cerebral ventricular guide cannula was implanted in the left lateral ventricle. The EEG electrodes were placed over the frontal and parietal cortexes. To measure Tbr, a calibrated 30-kOmega thermistor (model 44008; Omega Engineering, Stamford, CT) was implanted on the dura mater over the parietal cortex. For rats, an EMG electrode was implanted in the dorsal neck muscle. The patency of the icv guide cannula was verified in rats by the icv injection of 40 ng of angiotensin II (Sigma) in 4 µl PFS (27); this treatment evokes a drinking response. The leads from the EEG and EMG 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 1 (for rats) or 2 (for rabbits) wk of recovery, the animals were placed in experimental chambers (Hot Pack 352600; Philadelphia, PA). They were kept on a 12:12-h light-dark cycle (lights on at 0600 for rabbits and at 0900 for rats) at 21 ± 1°C (for rabbits) and 23 ± 2°C (for rats) ambient temperature. Animals had free access to water and food during the experiment.

Recording and Analysis

A flexible tether connecting the electrodes and thermistor led to an electronic swivel (SL6C; Plastics One, Roanoke, VA). For rabbits, 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. Because of technical problems, actual data size of Tbr was less than that of sleep data. The vigilance states of wakefulness, NREMS, and rapid eye movement sleep (REMS) were determined offline in 10-s epochs by criteria previously reported (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 a lack of body movements. In contrast, REMS was characterized by fast low-amplitude EEG waves, the appearance of rhythmic theta 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 the 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 graphical display. In addition, in experiment I, the number of NREMS and REMS episodes, and the mean episode lengths were determined by a computer program with the criterion that each episode lasted at least 30 s.

Experimental Protocols

Experiment I: effects of icv administration of IL-18 on spontaneous sleep in rabbits. Forty-three rabbits were used for this experiment. All rabbits received 25 µl PFS icv at dark onset on a control day. On the next experimental day, they also received one of the following three doses of IL-18 icv at dark onset: 10 (n = 9), 100 (n = 8), and 500 ng (n = 8). These injections took place between 1720 and 1800. Ten rabbits received 500 ng icv of IL-18 during the light period (injection time: 0830-0915); these rabbits received their control injection at light onset. Furthermore, another eight rabbits were injected with 500 ng of heat-inactivated (80°C, 60 min) IL-18 at dark onset. After injections, EEG, Tbr, and motor activity were recorded for the next 23 h.

Experiment II: effects of icv administration of IL-18 on spontaneous sleep in rats. All rats (total = 28) received 2.5 µl PFS icv on a control day. At dark onset on the next experimental day, they also received one of the following three doses of IL-18 icv: 1 (n = 7), 10 (n = 7), and 100 ng (n = 8). Furthermore, an additional six rats received heat-inactivated IL-18 (100 ng icv). These injections took place between 2020 and 2100. After injections, EEG, Tbr, and motor activity were recorded for the next 23 h.

Experiment III: effects of peripheral administration of IL-18 on spontaneous sleep in rats. A separate group of 22 rats was used in this experiment. All rats received 1 ml/kg of PFS ip on a control day. On the next experimental day, they also received one of the following three doses of IL-18 ip at dark onset: 0.3 (n = 8), 3 (n = 8), and 30 (n = 6). These injections took place between 2040 and 2100. After injections, EEG, Tbr, and motor activity were recorded for the next 23 h.

Experiment IV: effects of icv administration of anti-IL-18 antibody on spontaneous sleep in rabbits. Twenty-five rabbits were used in this experiment. All rabbits received 25 µl PFS icv on a control day. On the next experimental day, they also received one of the following two doses of control IgG icv: 2.5 (n = 8) or 25 µg (n = 9). On the third experimental day, they were injected with one of two doses of anti-IL-18 antibody icv: 2.5 (n = 8) or 25 µg (n = 9). These injections took place between 0830 and 0915. Furthermore, another eight rabbits underwent the same experiment using the 25-µg dose except that the injection time was between 1720 and 1800. After injections, EEG, Tbr, and motor activity were recorded for the next 23 h.

Experiment V: effects of icv administration of anti-IL-18 antibody on MDP-induced sleep in rabbits. On the control day, the rabbits were injected twice with PFS with the icv injections 15 min apart. The first injection volume was 15 µl, and the second injection volume was 10 µl. On the first experimental day, the animals were injected with 25 µg of control IgG or anti-IL-18 antibody, and 15 min later, they were injected with one of the following three doses of MDP: 25 (n = 8), 75 (n = 7), or 150 pmol (n = 8). Five days later, on the second experimental day, the same animals were injected icv with 25 µg of control IgG or anti-IL-18 antibody, and 15 min later, they were injected with one of the three doses of MDP. About one-half of the animals received control IgG + MDP on the first experimental day and anti-IL-18 antibody + MDP on the second experimental day. The other one-half of the animals received anti-IL-18 antibody + MDP on the first experimental day and control IgG + MDP on the second experimental day. All injections took place between 1700 and 1800. After injections, EEG, Tbr, and motor activity were recorded for the next 23 h.

Statistical Analysis

Statistical analyses were performed with 3-h time blocks. Two-way ANOVA for repeated measures followed by the Student-Newman-Keuls (SNK) test were used for all analyses. For the episode data, a separate ANOVA was used for each time block. A significant level of P < 0.05 was accepted.


    RESULTS
TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES

Experiment I: Effects of icv Administration of IL-18 on Spontaneous Sleep in Rabbits

The lowest dose (10 ng) of IL-18 failed to affect any of the sleep parameters measured (Table 1). In contrast, the two higher doses of IL-18 administered at dark onset significantly increased NREMS [ANOVA for the entire 23-h postinjection period; 100 ng: treatment effect, F(1,7) = 5.97, P < 0.05; 500 ng: treatment effect, F(1,7) = 12.71, P < 0.01 with time-treatment interaction, F(7,49) = 4.94, P < 0.001; Fig. 1B]. This effect was mainly due to an increase in the number of NREMS episodes [ANOVA treatment effect for 23 h; 100 ng: F(1,7) = 5.73, P < 0.05; 500 ng: F(1,7) = 12.80, P < 0.01; Table 2]. Heat-inactivated IL-18 (500 ng) failed to affect any of these parameters measured (Fig. 1A). NREMS also increased after the administration of IL-18 (500 ng) during the light period (Fig. 1C and Table 1). This effect was also due to an increase in the number of NREMS episodes [ANOVA for 23 h; F(1,9) = 6.52, P < 0.05]. In contrast, the mean duration of NREMS episodes tended to be shorter; this effect reached significance for the 500-ng dose during the dark period [ANOVA for 12-h dark period; F(1,9) = 5.42, P < 0.05; Table 2]. None of the doses of IL-18 administered at the dark onset affected REMS; however, REMS was inhibited after the administration of the 500-ng dose during the light period. This effect was transiently observed during 5-10 h postinjection [time-treatment interaction; F(7,63) = 2.92, P < 0.05] and it was due to a decrease in the number of REMS episodes [ANOVA for 9-h light period; F(1,9) = 8.79, P < 0.05; Fig. 1C, Tables 1 and 3]. EEG SWA increased during the initial 6-h postinjection period and then decreased compared with the control group after the 500-ng dose given at dark onset or during light period [ANOVA; 500 ng (dark onset): time-treatment interaction, F(7,49) = 2.75, P < 0.05; 500 ng (light period): time-treatment interaction, F(7,63) = 3.89, P < 0.01; Fig. 1, B and C]. IL-18 dose dependently increased Tbr [ANOVA for 23 h; 100 ng: time-treatment interaction, F(7,49) = 3.52, P < 0.01; 500 ng (dark onset): treatment effect, F(1,5) = 7.19, P < 0.05 with time-treatment interaction, F(7,35) = 3.12, P < 0.05; 500 ng (light period): treatment effect, F(1,8) = 11.21, P < 0.05; Fig. 1, B and C, and Table 1]. Heat-inactivated IL-18 failed to affect Tbr (Fig. 1A).

                              
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  		Table 1.   Effects of IL-18 on spontaneous sleep in rabbits



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  		Fig. 1.   Effects of intracerebroventricular (icv) injection of interleukin (IL)-18 on non-rapid eye movement sleep (NREMS), rapid eye movement sleep (REMS), electroencephalogram slow-wave activity (EEG SWA), and brain temperature (Tbr) in rabbits. Open circles and closed squares represent pyrogen-free saline (PFS) and IL-18 treatments, 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 EEG SWA data were expressed as a percentage of the control value. A: heat-inactivated IL-18 (500 ng) was injected at the dark onset. B: 500 ng of IL-18 were administered at the dark onset. C: 500 ng of IL-18 were administered during the light period.


                              
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  		Table 2.   Effects of IL-18 on NREMS episodes in rabbits


                              
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  		Table 3.   Effects of IL-18 on REMS episodes in rabbits

Experiment II: Effects of icv Administration of IL-18 on Spontaneous Sleep in Rats

The lowest dose (1 ng) of IL-18 given to rats did not affect any sleep parameter or Tbr. The two higher doses of IL-18 significantly increased NREMS [ANOVA for 23 h; 10 ng: treatment effect, F(1,6) = 6.04, P < 0.05; 100 ng: treatment effect, F(1,7) = 7.31, P < 0.05 with time-treatment interaction, F(7,49) = 5.41, P < 0.0001]. This effect was prominent during the initial 12-h dark period [ANOVA for 12 h; 100 ng: treatment effect, F(1,7) = 16.36, P < 0.01 with time-treatment interaction: F(3,21) = 3.08, P < 0.05] (Fig. 2A and Table 4). The 100 ng of IL-18 inhibited REMS during the 11-h light period [ANOVA for 23 h; 100 ng: time-treatment interaction, F(7,49) = 3.27, P < 0.01; ANOVA for 11-h light period; 100 ng: treatment effect, F(1,7) = 8.56, P < 0.05]. However, IL-18 slightly increased REMS during the initial 12-h light period [ANOVA for 12 h; 100 ng: treatment effect, F(1,7) = 8.45, P < 0.05; Table 4]. The 100 ng of IL-18 transiently increased EEG SWA during the initial 3-h postinjection [ANOVA for 23 h; 100 ng: time-treatment interaction, F(7,49) = 2.43, P < 0.05; SNK test for initial 3 h; q(5,49) = 4.00; Fig. 2A]. In rats, IL-18 also dose dependently increased Tbr, and this change reached significance after 100 ng icv of IL-18 [ANOVA for 23 h; 100 ng: treatment effect, F(1,6) = 9.44, P < 0.05; Fig. 2A]. Heat-inactivated IL-18 failed to affect any of the parameters measured (Fig. 2B and Table 4).


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  		Fig. 2.   Effects of icv injection of IL-18 on NREMS, REMS, EEG SWA, and Tbr in rats. Open circles and closed squares represent PFS and IL-18 treatment, respectively. A: 100 ng of IL-18 were injected at the dark onset. B: heat-inactivated IL-18 (500 ng) was injected at the dark onset.


                              
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  		Table 4.   Effects of IL-18 on spontaneous sleep in rats

Experiment III: Effects of Peripheral Administration of IL-18 on Spontaneous Sleep in Rats

The two lower doses of IL-18 given to rats systemically did not affect any sleep parameters or Tbr (data not shown). The highest systemic dose of IL-18 (30 µg/kg) slightly but significantly increased NREMS; rats had about 32 min extra NREMS during the 23-h recording period [ANOVA, treatment effect: F(1,5) = 8.77, P < 0.05; Fig. 3]. EEG SWA was significantly decreased after ip injection of the highest dose of IL-18 [ANOVA, treatment effect: F(1,5) = 7.21, P < 0.05; Fig. 3]. There were no changes in REMS or Tbr after any dose of IL-18 given ip to rats.


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  		Fig. 3.   Effects of intraperitoneal injection of IL-18 on NREMS, REMS, EEG SWA, and Tbr in rats. Open circles and closed squares represent PFS and 30 µg/kg of IL-18 treatments, respectively. Significant increases in NREMS and decrease in EEG SWA were observed.

Experiment IV: Effects of icv Administration of Anti-IL-18 Antibody on Spontaneous Sleep in Rabbits

Compared with the control IgG group, 2.5 and 25 µg of anti-IL-18 antibody induced a suppression of NREMS by 22.8 and 21.2 min duration during the 23-h recording period, respectively, after the injections during the light period (Fig. 4). However, these changes did not reach significance. Anti-IL-18 also failed to induce significant changes in REMS, EEG SWA, or Tbr. Anti-IL-18 did not affect any parameters measured after the injection at the dark onset (data not shown).


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  		Fig. 4.   Anti-IL-18 antibody failed to affect spontaneous sleep in rabbits. Open circles and closed squares represent control IgG and anti-IL-18 treatments, respectively. A: 2.5 µg. B: 25 µg.

Experiment V: Effects of icv Administration of Anti-IL-18 Antibody on MDP-Induced Sleep in Rabbits

All three doses of MDP in combination with control IgG enhanced NREMS [ANOVA for the 23-h entire period; 25 pmol: treatment effect, F(2,14) = 4.46, P < 0.05 with time-treatment interaction, F(14,98) = 2.42, P < 0.01; 75 pmol: treatment effect, F(2,12) = 9.95, P < 0.01 with time-treatment interaction, F(14,84) = 3.45, P < 0.001; 150 pmol: treatment effect, F(2,14) = 6.90, P < 0.01 with time-treatment interaction, F(14,98) = 3.75, P < 0.0001; Table 5]. The NREMS-enhancing actions of the low dose of MDP were not significantly inhibited by the anti-IL-18 antibody [SNK test for 25 pmol: control vs. IgG + MDP, q(3,14) = 4.10, P < 0.05; IgG + MDP vs. anti-IL-18 + MDP, q(2,14) = 1.17, not significant; control vs. anti-IL-18 + MDP, q(2,14) = 2.93, not significant]. In contrast, after the higher doses of MDP, which induced greater NREMS responses than the lower dose, anti-IL-18 attenuated the MDP-induced NREMS responses [SNK test for 75 pmol: control vs. IgG + MDP, q(3,12) = 6.30, P < 0.05; IgG + MDP vs. anti-IL-18 + MDP, q(2,12) = 3.46, P < 0.05; control vs. anti-IL-18 + MDP, q(2,12) = 2.54, not significant; SNK test for 150 pmol: control vs. IgG + MDP, q(3,14) = 5.21, P < 0.05; IgG + MDP vs. anti-IL-18 + MDP, q(2,14) = 3.18, P < 0.05; control vs. anti-IL-18 + MDP, q(2,14) = 2.03, ns; Fig. 5 and Table 5]. The NREMS-promoting effects of MDP and the inhibitory actions of anti-IL-18 on MDP-enhanced NREMS were most obvious during the initial 12-h dark period [ANOVA, treatment effects for 12-h dark period; 25 pmol: F(2,14) = 5.82, P < 0.05; 75 pmol: F(2,12) = 10.33, P < 0.01; 150 pmol: F(2,14) = 12.60, P < 0.001; SNK test for 25 pmol: control vs. IgG + MDP, q(3,14) = 4.73, P < 0.05; IgG + MDP vs. anti-IL-18 + MDP, q(2,14) = 1.55, not significant; control vs. anti-IL-18 + MDP, q(2,14) = 3.18, P < 0.05; SNK test for 75 pmol: control vs. IgG + MDP, q(3,12) = 6.40, P < 0.05; IgG + MDP vs. anti-IL-18 + MDP, q(2,12) = 2.74, not significant; control vs. anti-IL-18 + MDP, q(2,12) = 3.67, P < 0.05; SNK test for 150 pmol: control vs. IgG + MDP, q(3,14) = 7.10, P < 0.05; IgG + MDP vs. anti-IL-18 + MDP, q(2,14) = 3.43, P < 0.05; control vs. anti-IL-18 + MDP, q(2,14) = 3.67, P < 0.05]. The two higher doses of MDP significantly suppressed REMS, and the pretreatment of the rabbits with anti-IL-18 significantly antagonized this effect in the 75-pmol MDP group but not in the 150-pmol MDP group [ANOVA for 23-h entire period; 75 pmol: treatment effect, F(2,12) = 4.87, P < 0.05 with time-treatment interaction, F(14,84) = 1.88, P < 0.05; 150 pmol: treatment effect, F(2,14) = 3.95, P < 0.05 with time treatment interaction, F(14,98) = 2.85, P < 0.01; SNK test for 75 pmol: control vs. IgG + MDP, q(3,12) = 4.10, P < 0.05; IgG + MDP vs. anti-IL-18 + MDP, q(2,12) = 3.47, P < 0.05; control vs. anti-IL-18 + MDP, q(2,12) = 0.64, not significant; SNK test for 150 pmol: not significant; ANOVA, treatment effect for 11-h light period; 75 pmol: F(2,12) = 7.68, P < 0.01; 150 pmol: F(2,14) = 10.40, P < 0.01; SNK test for 75 pmol: control vs. IgG + MDP, q(3,12) = 5.39, P < 0.05; IgG + MDP vs. anti-IL-18 + MDP, q(2,12) = 3.84, P < 0.05; control vs. anti-IL-18 + MDP, q(2,12) = 1.55, not significant; SNK test for 150 pmol: control vs. IgG + MDP, q(3,14) = 6.03, P < 0.05; IgG + MDP vs. anti-IL-18 + MDP, q(2,14) = 1.03, not significant; control vs. anti-IL-18 + MDP, q(2,14) = 5.00, P < 0.05; Fig. 5 and Table 5]. EEG SWA tended to increase during the initial 8 h after the administration of MDP. Changes in the 25- and 75-pmol groups reached significance but did not in the 150-pmol group [ANOVA for 23 h; 25 pmol: time-treatment interaction, F(14,98) = 3.41, P < 0.001; 75 pmol: time-treatment interaction, F(14,84) = 4.69, P < 0.0001; 150 pmol: time-treatment interaction, F(14,98) = 1.66, not significant]. Anti-IL-18 antibody did not attenuate MDP-enhanced EEG SWA (Fig. 5). Tbr significantly increased after all doses of MDP treatment, and the pretreatment of the rabbits with anti-IL-18 slightly attenuated this effect. However, the attenuation of MDP-induced fevers failed to reach significance [ANOVA for 23-h; 25 pmol: treatment effect, F(2,10) = 11.53, P < 0.01 with time-treatment interaction, F(14,70) = 5.85, P < 0.0001; 75 pmol: treatment effect, F(2,12) = 9.10, P < 0.01 with time treatment interaction: F(14,84) = 4.23, P < 0.0001; 150 pmol: F(2,14) = 20.77, P < 0.0001; SNK test for 25 pmol: control vs. IgG + MDP, q(3,10) = 6.68, P < 0.05; IgG + MDP vs. anti-IL-18 + MDP, q(2,10) = 2.30, not significant; control vs. anti-IL-18 + MDP, q(2,10) = 4.39, P < 0.05; SNK test for 75 pmol: control vs. IgG + MDP, q(3,12) = 5.83, P < 0.05; IgG + MDP vs. anti-IL-18 + MDP, q(2,12) = 1.56, not significant; control vs. anti-IL-18 + MDP, q(2,12) = 4.27, P < 0.05; SNK test for 150 pmol: control vs. IgG + MDP, q(3,14) = 8.77, P < 0.05; IgG + MDP vs. anti-IL-18 + MDP, q(2,14) = 2.55, not significant; control vs. anti-IL-18 + MDP, q(2,14) = 6.52, P < 0.05] (Fig. 5 and Table 5).

                              
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  		Table 5.   Anti-IL-18 antibody attenuates MDP-induced sleep and fever in rabbits



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  		Fig. 5.   Effects of anti-IL-18 on muramyl dipepetide (MDP)-induced sleep and Tbr. Closed circles, open circles, and closed squares represent PFS + PFS, control IgG (25 µg) + MDP (75 pmol), and anti-IL-18 (25 µg) + MDP (75 pmol) treatments, respectively. Anti-IL-18 significantly attenuated MDP-induced NREMS and MDP-suppressed REMS but failed to affect MDP-induced EEG SWA and fever.


    DISCUSSION
TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES

The major finding in the present study is that IL-18 enhances NREMS. The mechanism by which IL-18 enhances of NREMS is unknown. However, other sleep regulatory substances (SRSs) are likely to be involved in IL-18-induced sleep. IL-18 can trigger a cascade of proinflammatory cytokines. For instance, IL-18 stimulates TNF-alpha gene expression and thereby induces IL-1beta (45). Furthermore, the IL-18-IL-18 receptor complex activates NF-kappa B (reviewed in Ref. 7). NF-kappa B is involved in the expression of several SRSs and their associated molecules, including IL-2 (16), COX-2 (17, 33), inducible NOS (10), the adenosine A1 receptor (34), IL-1beta , TNF-alpha (reviewed in Refs. 2 and 35), and nerve growth factor (11, 14, 15; and sleep effects of these substances reviewed in Ref. 24). Sleep deprivation also promotes NF-kappa B activation (3). Moreover, a cell-permeable NF-kappa B inhibitor peptide inhibits spontaneous and IL-1beta -induced sleep (26). Furthermore, IL-18 induces IFNgamma -expression. IFNgamma can suppress the expression of IL-10, an anti-inflammatory cytokine (4, 9). IL-10 inhibits spontaneous sleep in rats and rabbits (28, 42).

Another important finding of this study is that anti-IL-18 antibodies attenuate MDP-induced NREMS. Previously, we showed that pretreatment with the IL-1-receptor fragment (52) or the IL-1 type I soluble receptor (18) or the IL-1-receptor antagonist (18) attenuates MDP-induced NREMS. Furthermore, we also reported that pretreatment with the TNF-receptor fragment also inhibited MDP-induced NREMS (53). Therefore, the somnogenic effects of MDP are partially mediated by IL-1 and TNF production. The present study suggests that IL-18 is also involved in the sleep-promoting effects of MDP. Thus, after the two highest doses of MDP, anti-IL-18 attenuated MDP-induced NREMS. That anti-IL-18 antibodies failed to significantly inhibit MDP-induced NREMS after the lower dose of MDP could suggest that the lower dose of MDP preferentially induced IL-1 and/or TNF production and only higher doses of MDP elicited IL-18 production. Thus the relative contribution of IL-18 to the MDP-induced sleep may change with the dose of MDP. Finally, IL-18 may also be important in sleep responses associated with other types of pathology. For instance, IL-18 plasma levels correlate with disease activity in systemic lupus erythematosus (61); such patients also have sleep disturbances (60).

Whether IL-18 is involved in physiological sleep regulation remains unclear. If IL-18 is involved in physiological sleep regulation, immunoneutralization of IL-18 should have reduced spontaneous sleep. However, the present study showed little inhibitory effect of anti-IL-18 antibody on normal sleep. In contrast, inhibition of endogenous IL-1 or TNF-alpha reduces spontaneous sleep in rabbits and rats. Therefore, it is possible that IL-18 is less important in physiological sleep regulation than IL-1 or TNF-alpha . However, this study has some limitations. IgG itself can induce cytokine production, including IL-1 (1). Indeed, a high dose of anti-IL-1 antibody enhances NREMS in rats (37). Thus we could not give a very high concentration of anti-IL-18 antibody in this study. Although the control IgG used in this experiment did not show any sleep and fever responses compared with PFS injection, it is possible that the promotion of very small amounts of other cytokines induced by anti-IL-18 antibody masked the inhibitory effect of IL-18. Regardless, current data suggest that IL-18 plays a minor role in physiological sleep regulation but does contribute to sleep responses induced by microbial agents.

EEG SWA is thought to reflect the intensity of NREMS. For instance, it markedly increases during the deep sleep after sleep deprivation (44). In this study, IL-18 increased EEG SWA in rabbits during the initial 6 h after administration and then decreased EEG SWA. This effect is similar to those observed after IL-1beta and TNF-alpha . Takahashi et al. (52) reported that EEG SWA in rabbits significantly increased during 4-6 h after icv injection of IL-1beta and then decreased compared with the control. Furthermore, in rats, icv administration of IL-18 transiently increases EEG SWA, whereas EEG SWA decreases after ip administration. These results are similar to those observed after IL-1beta ; EEG SWA decreases after ip administration of IL-1beta (13) and increases after icv administration in rats (41). It is not known why the effects of IL-18 and IL-1beta on EEG SWA depend on the route of injections. In the current study, EEG SWA also increased after MDP administration, and this result confirmed our previous results (52, 53, and reviewed in Ref. 43). However, MDP-induced EEG SWA was not antagonized by the anti-IL-18 antibody. In contrast, the pretreatment of rabbits with the IL-1-receptor fragment or the TNF-receptor fragment attenuates MDP-induced EEG SWA (52, 53). Therefore, our current results support the notion that the mechanisms involved in generating EEG SWA are different from those regulating NREMS (48) and that IL-18 may not be involved in the mechanism of MDP-enhanced EEG SWA.

In the present study, IL-18 significantly inhibited REMS, and this effect was light/dark cycle dependent. High NREMS-promoting doses of IL-1beta (e.g., 10 ng in rabbits) and TNF-alpha (e.g., 250 ng in rabbits) also inhibit REMS (51); it is thus possible that this effect of IL-18 may be mediated by the induction of IL-1beta or TNF-alpha . Furthermore, in this study, the 75 pmol of MDP-suppressed REMS were reversed by the anti-IL-18 antibody; however, this effect was not observed after the high dose (150 pmol) of MDP administration. Takahashi et al. (52, 53) also reported that pretreatment with the IL-1-receptor fragment or TNF-receptor fragment reversed MDP-suppressed REMS. Therefore, the current study suggests that IL-18, in addition to IL-1beta and TNF-alpha , may be involved in the mechanism of MDP-suppressed REMS.

The biological activities of IL-18 are lost by heat treatment (31), whereas endotoxin, a common contaminant of recombinant products, is not inactivated under this condition (reviewed in Ref. 49). The febrile and sleep responses observed after IL-18 injection are thus considered to be biological actions of IL-18. Although proinflammatory cytokines have somnogenic and pyrogenic properties, these effects depend on separate mechanisms (reviewed in Ref. 23). For example, antipyretics block IL-1-induced fever but not sleep (25). Inhibitors of NOS inhibit IL-1-induced sleep but not fever (reviewed in Ref. 23). Another proinflammatory cytokine, IL-6, induces dose-related fevers without affecting sleep (39). Similarly, substances that reduce Tbr can either enhance sleep (adenosine agonists) (56) or inhibit sleep (alpha -melanocyte-stimulating hormone) (40). Furthermore, increases in Tbr induced by passive heating are associated with concurrent decreased NREMS (30). Such findings coupled with the current finding that anti-IL-18 inhibited MDP-induced NREMS responses but not fever clearly support the notion that IL-18-induced fevers do not induce secondary NREMS responses.

It is likely that fevers result from the induction of endogenous pyrogens like PGs. For example, icv injection of PGE2 induces fever in rabbits (21). As mentioned above, IL-18 activates NF-kappa B, and NFkappa B is involved in the expression of COX-2, a rate-limiting enzyme for PG production (17, 33). However, in human peripheral blood mononuclear cells, IL-18 does not induce COX-2 or PGE2 (46). Furthermore, the anti-IL-18 antibody had little effect on Tbr under physiological conditions or after the administration of MDP. We also previously reported that pretreatment with the IL-1-receptor fragment or the IL-1-soluble receptor had little effect on MDP-induced fever (18, 52), although the TNF-receptor fragment markedly inhibited MDP-induced fever (53). Therefore, it is likely that TNF-alpha is a primary factor in MDP-induced fever and IL-18 is not a critical factor for regulation of body temperature or febrile responses during infection.

In summary, IL-18 seems to play an important role in the sleep responses induced by microbial products. Furthermore, current data support the hypothesis that the cytokine network in the brain regulates sleep.


    ACKNOWLEDGEMENTS

We thank Drs. J. Majde and C. A. Dinarello for suggesting that we investigate the somnogenic properties of IL-18.


    FOOTNOTES

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

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

Received 27 February 2001; accepted in final form 17 May 2001.


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Am J Physiol Regul Integr Comp Physiol 281(3):R828-R838
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