Cytokines and Sleep

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As will be discussed in more detail below, sleep is affected by infection, a primary driving force for nonspecific inflammation and cytokine production. It should come as no surprise therefore that a number of groups have examined in detail the evidence for an interaction between modulation of cytokine production and altered sleep behavior. This is reviewed in more detail elsewhere in this volume, but some brief mention is necessary before further discussion of altered sleep in disease.

As a precursor to an introduction of the role of cytokines in altering sleep behavior, consider the changes in cytokines reported in a number of sleep disorders. The latter are quite common in the general population and are associated with significant medical, psychological, and social disturbances. Deep sleep has an inhibitory influence on the hypothalamic-pituitary-adrenal (HPA) axis, in contrast to activation of the HPA axis or administration of glucocorticoids, which has been reported to lead to arousal and sleeplessness. Not surprisingly then, insomnia, the most common sleep disorder, is associated with a 24-h increase of corticotropin and cortisol secretion, consistent with a disorder of central nervous system hyperarousal

(Vgontzas and Chrousos 2002). Sleepiness and generalized fatigue, both prevalent in the general population, are now thought to be associated with elevations in the levels of the proinflammatory cytokines IL-6 and TNF-a, both of which are also elevated in disorders associated with excessive daytime sleepiness, including sleep apnea (Mills and Dimsdale 2004), narcolepsy, and idiopathic hypersomnia. Indeed, sleep deprivation reportedly leads to sleepiness and daytime hypersecretion of IL-6 (Vgontzas et al. 2002). Hu et al. performed a similar investigation in mice, examining serum cytokine and chemokine levels following 36 of sleep deprivation, or after exposure to a known physical stressor (rotational stress) (Hu et al. 2003). Changes in inflammatory cytokines/chemokines (IL-ip, TNF-a, IL-1ra, IL-6, and MIP- ip, MCP-1) were observed following each manipulation, but the qualitative and quantitative patterns differed in the two scenarios. Only physical stress was associated with measured increases in serum corticosterone levels, and with independent evidence (using in vitro immune allo stimulation) for a generalized immunosuppression secondary to the experimental manipulation. This group concluded that altered cytokine production following sleep perturbation occurred by a different mechanism from that (HPA axis) attributed to stress per se.

Given that independent studies have suggested that IL-ip and TNF-a promote slow-wave sleep (SWS), whereas IL-10 inhibits the synthesis of both cytokines and promotes waking, Toth et al. studied mice in which the gene encoding IL-10 had been deleted by homologous recombination, IL-10K0 mice (Toth and Opp 2001). Under basal conditions, IL-10K0 mice spent more time in SWS during the dark phase of the light-dark cycle than did their genetically intact counterparts. While the two groups of animals had comparable responses after treatment with IL-1, IL-10, or influenza virus, the response to LPS injection was quite different. In the IL-10 KO mice, LPS induced an initial transient increase and a subsequent prolonged decrease in SWS, along with a marked hypothermic response, observations which were not seen in the wild-type controls. The authors concluded that IL-10 plays a crucial role in the regulation of normal sleep behavior patterns. Kushikata et al. also has reported on another cytokine, IL-4, which, in simple immunological terms, is often thought to act to counter some of the effects of inflammatory and type-1 cytokines. In this study spontaneous sleep was observed in rabbits receiving one of four doses of IL-4 (0.25, 2.5, 25, and 250 ng) injected intracerebroventricularly during the rest (light) period, and another group receiving 25 ng during the active (dark) cycle (Kushikata, Fang, Wang, and Krueger 1998). Appropriate time-matched control injections of saline were performed in the same rabbits on different days. IL-4 administered at dark onset had no effect on sleep. In contrast, the three highest doses of IL-4 inhibited spontaneous non-REM sleep if the IL-4 was given during the light cycle, while the highest dose of IL-4 (250 ng) also decreased REM sleep.

Other inflammatory cytokines, besides IL-1p and TNF-a are now thought to be important in sleep induction. Central administration of rat recombinant IL-6 (100 and 500 ng) increased NREM sleep in rats, with evidence for a subsequent suppression of NREM sleep in the aftermath. Moreover, the effect was not related to a simple pyrogen effect, since IL-6-induced febrile responses at doses lower (50 ng) than those required to alter sleep. REM sleep was not altered by any of the doses of IL-6 tested (Hogan, Morrow, Smith, and Opp 2003). However, when the authors attempted to gain further corollary support for the role for IL-6 using central administration of monoclonal or polyclonal anti-rat IL-6 antibodies, none of the parameters monitored in the study were changed. Thus, while IL-6 may possess sleep modulatory properties, the authors suggest it is unlikely to be involved in the regulation of spontaneous sleep in healthy animals since antagonizing the IL-6 system using antibodies did not alter sleep. A different conclusion was reached by Vgontzas et al. from circadian studies in humans (Vgontzas, Bixler, Lin, Prolo, Trakada, and Chrousos 2005). It has been reported in the human population that IL-6 is elevated in disorders of excessive daytime sleepiness such as narcolepsy and obstructive sleep apnea, correlating positively with body mass index and thus acting potentially as a mediator of sleepiness in obesity. Secretion of this cytokine is also reported to be stimulated by total acute or partial short-term sleep loss, again possibly reflecting the increased sleepiness experienced by sleep-deprived individuals. Measurement of the 24-h secretory pattern of IL-6 in healthy young adults shows that IL-6 is secreted in a biphasic circadian pattern with two nadirs at about 08.00 and 21.00, and two peaks at about 19.00 and 05.00 h. Following sleep deprivation or in disorders with disrupted sleep performance (insomnia) IL-6 peaks during the day and, concomitant with altered cortisol secretion, contributes to sleepiness and deep sleep (when cortisol levels are low) or feelings of tiredness, fatigue and poor sleep (when cortisol levels are high). Furthermore, Vgontzas et al. have reported that IL-6 is somnogenic in rats, with a diurnal (secretion) rhythm that follows the sleep/wake cycle in these animals, supporting an important role for IL-6 as a mediator of sleep behavior.

Other groups have concentrated less on the inflammatory cytokines (or their counter regulatory cytokines) referred to above, and more on their receptors and/or other molecules in sleep behavior. Thus, Haack et al. have characterized concentrations of soluble TNFrs and IL-2r during normal sleep and wakefulness, as well as during a 24-h sleep deprivation (Haack, Pollmacher, and Mullington 2004). Plasma levels of the TNFr p55, TNFr p75, and IL-2r remained essentially unchanged during nocturnal sleep and nocturnal wakefulness, although they did observe significant diurnal variations for both TNFr p55 and TNFr p75, but not IL-2r. Peak levels for both TNFrs occurred ~6:00 in the morning, well before that for cortisol, and fluctuated inversely with the diurnal rhythm of temperature, consistent with the hypothesis that diurnal variations in levels of TNFrs plays a role in normal diurnal temperature regulation. Finally, OConnor et al. recently reported on their investigations into the role for high mobility group box 1 (HMGB1), an abundant, highly conserved cellular protein, widely known as a nuclear DNA-binding protein, in the regulation of sleep. HMGB1 is implicated as a proinflammatory cytokine with a known role as a late mediator of endotoxin lethality, along with a defined ability to stimulate release of proinflammatory cytokines from monocytes (OConnor et al. 2003). Intracerebroventricular administration of HMGB I has been reported to increase TNF-a expression in mouse brain and induce aphagia and taste aversion. OConnor et al. also showed that intracerebroventricular injections of HMGB1-induced fever and hypothalamic IL-1 in rats, while intrathecal administration of HMGB1 lowered the response threshold to calibrated stimuli. While LPS administration elevated IL-1 and TNF-a mRNA levels in various brain regions, HMGB1 mRNA was unchanged. While not completely discounting the possibility that HMGB1 protein is released in brain in response to LPS, their data does imply that HMGB1 has proinflammatory characteristics within the CNS (and thus potentially sleep-promoting properties), which may be triggered independent of LPS signaling.

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