Effect of Modulation of Immune System on Sleep 831 Overview

It is well known that nearly all infectious diseases and chronic inflammatory disorders affect sleep. Most individual have experienced the almost irresistible desire for sleep with the onset of "flu." Further, altered of sleep were described in infected rabbits (Toth and Krueger 1988) and rats (Kent, Price, and Satinoff 1988). These changes in sleep in response to infectious challenge are facet of the acute phase response (APR) (Krueger and Majde 1990; Krueger et al. 1994; Majde and Krueger 2005). Many kind of infection like viral, bacterial, fungal, or parasitic, have changes in amount of non-rapid eye movement sleep (NREMS) or rapid eye movement sleep (REMS) (Toth 1999). Excess sleep is reported in patients with infectious mononucleosis (Lambore, McSherry, and Kraus 1991), HIV-1 (Norman et al. 1992), rhinovirus-induced common cold (Drake, Roehrs, Royer, Koshorek, Turner, and Roth 2000). The degree of sleep alteration is depending on kind of infection. For example, sleep pattern in patients with infectious mononucleosis is not changed (Guilleminault and Mondini 1986). Patients seropositive for human immunodeficiency virus develop increase slow wave sleep even in the lack of clinical symptoms (Norman et al. 1992). Conversely, infection of rabies virus caused almost total loss of NREMS in mouse or human (Gourmelon, Briet, Clarencon, Court, and Tsiang 1991).

Influenza is one of common model as infection-related sleep alteration. Large dose of influenza virus given intravenously increased NREMS with fever rapidly in rabbits, whereas inactivated virus had not any effect on sleep (Kimura-Takeuchi, Majde, Toth, and Krueger 1992). Pretreatment of influenza virus (Kimura-Takeuchi et al. 1992) or synthetic double-stranded RNA of the virus inhibits these APR. These results suggest that pretreatment of either the virus itself or the dsRNA would products some substance that is able to inhibit the virus-induced APR.

8.3.2 Microbial Products, Cytokines, Sleep

Microbial-induced responses are mediated via enhanced cytokine production in which including somnogenic cytokine. Several substances or conditions have the capacity to enhance IL-ip and/or TNF-a. For example, infectious diseases increase NREMS and up-regulate IL-ip receptor (Alt et al. 2005; Aho, McNulty, and Coussens 2003). Pathological stimuli such as lipopolysaccharide or neurotropic virus enhance brain TNF-a production (Lang, Silvis, Deshpande, Nystrom, and Frost 2003). Several cytokines are involved in sleep regulation (Table 8.1).

Table 8.1. Cytokines involved in sleep regulation._

A. Somnogenic cytokines

IL-ip

TNF-a

IL-2

IL-15

IL-18

Epidermal growth factor

Acidic fibroblast growth factor

Neurotrophin 1 (nerve growth factor)

Neurotrophin 2 (brain-derived neurotropic factor)

Neurotrophin 3

Neurotrophin 4

Glia-derived neurotrophic factor Platelet Activating Factor Interferon-a Interferon-y

Granulocyte-macrophage colony stimulating factor Granulocyte stimulating factor

B. Anti-Somnogenic cytokines

IL-4

IL-10

IL-13

Transforming growth factor p Insulin-like growth factor Soluble TNF receptor Soluble IL-1 receptor

8.3.3 Proinflammatory Cytokines on Sleep

The role of humoral mechanisms on sleep regulation has been considered across centuries. Substance-based theories on the humoral mechanism were reported at early last century using sleep-deprived dogs by two independent laboratories,

Ishimori in Japan (Ishimori 1909) and Pieron in France. At 1960s, many studies have focused again on the humoral mechanism.

Pappenheimer, Koski, Fencl, Karnovsky, and Krueger (1975) reported that if cerebrospinal fluid obtained from sleep-deprived goat administered into rats, the rats dramatically increased sleep. The unidentified sleep-inducible substance was referred as factor S. Later, factor S was a muramyl peptide derived from bacterial peptideglycan that chemically unique cell wall component of all bacteria. Muramyl dipeptide and the factor S related peptideglucans were all induce IL-1ß, a key immunoregulatory cytokine. IL-1ß was shown as a potent somnogen and pyrogen (Majde et al. 2005; Opp 2004).

Since then, much evidence showed that proinflammatory cytokines such as IL-1ß or TNF-a are key elements in sleep regulation. Administration of exogenous these substances induce increased in NREMS in various species (reviewed in Krueger, Majde, and Obal (2003)). Administration of exogenous TNF-a (Fang, Wang, and Krueger 1997; Kapas et al. 1992) or IL-1 (Fang, Wang, and Krueger 1998; Krueger, Walter, Dinarello, Wolff, and Chedid 1984) enhances NREMS in a variety of species. Normal sleep pattern was maintained following these substance administrations. Animals have a normal circadian cycle of wakefulness, NREMS, and REMS and easily aroused if disturbed.

Also, changes in brain temperature accompanied with sleep was maintained as normal, thus, autonomic changes with sleep stage was persist (Walter, Davenne, Shoham, Dinarello, and Krueger 1986). Both IL-1ß and TNF-a induced an enhancement of electroencephalographic (EEG) slow wave activity (SWA), a parameter of sleep intensity (Pappenheimer et al. 1975). If either IL-1ß (Yasuda, Yoshida, Garcia-Garcia, Kay, and Krueger 2005) or TNF-a (Yoshida, Peterfi, Garcia-Garcia, Kirkpatrick, Yasuda, and Krueger 2004) applied to rat cerebral cortex locally, SWA was enhanced only at the ipsilaterally. In addition, locally application of soluble receptor fragment, inhibitor of both IL-1ß (Yasuda et al. 2005) and TNF-a (Yoshida et al. 2004), inhibited the enhancement following sleep deprivation. These results showed IL-1ß and TNF-a have a capability of physiological sleep.

IL-1 and TNF and their receptor are present in normal brain (Krueger et al. 1999). Both IL-1 and TNF mRNA have diurnal rhythm. For example, in rats, IL-1ß mRNA levels in the hypothalamus, cerebral cortex, brainstem, and hippocampus are highest during peak sleep periods (daytime) (Taishi, Bredow, Guha-Thakurta, Obal, and Krueger 1997) and increase in the brain after sleep deprivation (Mackiewicz, Sollars, Ogilvie, and Pack 1996). In cats, IL-1 cerebrospinal fluid levels varied in phase with the sleep-wake cycle (Lue, Bail, Jephthah-Ochola, Carayanniotis, Gorczynski, and Moldofsky 1988). TNF bioactivity levels in rat hypothalamus and cortex are about 10-fold greater during peak sleep periods than during waking hours (Floyd and Krueger 1997). After sleep deprivation, brain IL-1 and TNF mRNA were increased (Taishi et al. 1998). Plasma levels of IL-1 are highest at onset of sleep in human (Moldofsky, Lue, Eisen, Keystone, and Gorczynski 1986). Circulating levels of IL-1 and TNF are also affected by the sleep-wake cycle and sleep deprivation (Entzian, Linnemann, Schlaak, and Zabel 1996; Gudewill, Pollmacher, Vedder, Schreiber, Fassbender, and Holsboer 1992; Hohagen et al. 1993; Uthgenannt, Schoolmann, Pietrowsky, Fehm, and Born 1995), and their highest levels are associated with enhanced sleep or sleepiness. These data strongly suggest that both IL-1 and TNF are involved in sleep regulation.

Some condition that induces of IL-1 or TNF also increases excess NREMS. Therefore, microbial product such as muramyl peptides, viral double-stranded RNA, and lipopolysuccharide induce IL-1 and TNF, and sleep (Krueger and Majde 1994). Some inflammatory mediator involved in sleep regulation. Platelet activating factor (PAF) is one of a key inflammatory mediator (Mathiak, Szewczyk, Abdullah, Ovadia, and Rabinovici 1997). PAF and its receptor are found in brain (Bito, Kudo, and Shimizu 1993; Dray et al. 1989; Aihara, Ishii, Kume, and Shimizu 2000; Brodie 1994), and it affects or is affected of the production IL-1ß (Fernandes et al. 2005), TNF-a (Fernandes et al. 2005; Rola-Pleszczynski and Stankova 1992). PAF interacts production of several other sleep-regulatory substances such as nerve growth factor (Brodie, 1995), brain-derived neurotrophic factor and neurotrophin-3 (Noga, Englmann, Hanf, Grutzkau, Seybold, and Kunkel 2003), nitric oxide (Zhu and He 2005; Mariano, Bussolati, Migliori, Russo, Triolo, and Camussi 2003), prostaglandins (Teather, Lee, and Wurtman 2002; Teather and Wurtman 2003), and prolactin (Camoratto and Grandison 1989). Indeed, PAF enhances NREMS in rabbits (Kushikata, Fang, and Krueger 2006). These results are consistent with the hypothesis that the brain cytokine network is involved in physiological sleep regulation.

It is a common experience and an established experimental finding that mild increases in ambient temperature enhance sleep (Obal, Alfoldi, and Rubicsek 1995; Shoham and Krueger 1988; Szymusiak, Danowski, and McGinty 1991). Although the exact mechanisms of this effect remain unknown, many data suggest that sleep regulation and thermoregulation are closely linked (Krueger and Takahashi 1997). Many sleep-regulatory substances, including IL-1ß and TNF-a, also affect thermoregulation (Krueger et al. 1995). A tumor necrosis factor receptor fragment (TNF-RF) inhibits warm-induced sleep responses in rabbits (Takahashi and Krueger 1997). However, somnogenic and pyrogenic capacity of both IL-1ß and TNF-a are separable. For example, doses of both substances that increase of NREMS are lower than their pyrogenic doses. Coadministration of an antipyretic with IL-1 blocks IL-1-induced fever but not IL-1-induced sleep (Krueger et al. 1984). Inhibition of NO synthase with arginine analogs blocks IL-1-induced sleep but not IL-1-induced fever (Kapas, Fang, and Krueger 1994).

Inhibition of either IL-1ß or TNF-a decrease amount of NREMS. The regulation of proinflammatory cytokines is complex and, in brain, not very well understood. Nevertheless, some substances associated with specific cytokines such as the IL-1RA or the TNF and IL-1 soluble receptors seem to act as endogenous antagonists and indeed, these substances inhibit spontaneous sleep (Opp, Postlethwaite, Seyer, and Krueger 1992; Takahashi, Kapas, Fang, Seyer, Wang, and Krueger 1996; Takahashi, Kapas, and Krueger 1996). The blockade of TNF or IL-1 using antibodies (Opp and Krueger 1994; Takahashi et al. 1997) inhibits spontaneous sleep. These inhibitors also inhibit sleep rebound after sleep deprivation (Opp et al. 1994; Takahashi, Fang, Kapas, Wang, and Krueger 1997), the excess NREMS associated with acute mild increases in ambient temperature (Takahashi et al. 1997; Kushikata, Takahashi, Wang, Fang, and Krueger 1998) and the excess NREMS associated with administration of bacterial products (Takahashi et al. 1996). Mutant mice lacking the

TNF 55-kDa receptor or mice lacking the IL-1 type 1 receptor sleep less than their respective strain controls (Fang et al. 1997, 1998).

8.3.4 Anti-Inflammatory Cytokines on Sleep

There is a class of anti-inflammatory cytokines, which includes IL-4, IL-10, and IL-13, transforming growth factor-p-1 (TGF P). Each of these cytokines has a unique set of biological activities though both, in one manner or another, inhibit proinflammatory cytokines thus they could inhibit sleep. Indeed, IL-4 inhibits rabbit spontaneous sleep (Kushikata, Fang, Wang, and Krueger 1998), IL-10 inhibits spontaneous NREMS in rats (Opp, Smith, and Hughes 1995) and rabbits (Kushikata, Fang, and Krueger 1999), and IL-13 and TGF P inhibit sleep (Kubota, Fang, Kushikata, and Krueger 2000), thereby providing further evidence that proinflammatory cytokines are involved in physiological sleep regulation. IL-10 inhibits IL-1P and TNF-a (Kanaan, Poole, Saade, Jabbur, and Safieh-Garabedian, 1998; Fiorentino, Zlotnik, Mosmann, Howard, and O'Garra, 1991). IL-10 inhibits IL-1P and TNF-a production (Thomassen, Divis, and Fisher, 1996) and increases the production of the IL-1RA (Joyce, Steer, and Kloda 1996). IL-10 inhibits induction of IL-1 receptor type I and II gene expression (Dickensheets and Donnelly 1997). Further, exogenous IL-10 inhibits production or release of other substances implicated in sleep regulation, e.g., nitric oxide (Dugas, Palacios-Calender, Dugas, Riveros-Moreno, Delfraissy, Kolb, and Moncada 1998; Laffranchi, and Spinas, 1996) and insulin (Laffranchi et al. 1996). In addition, IL-10 increases sleep-inhibitory substances production, e.g., corticotrophin releasing factor (Stefano, Prevot, Beauvillain, and Hughes, 1998).

8.3.5 Molecular Level Modulation of Cytokines on Sleep

Sleep regulation is dependent, in part, on changes in gene expression and production of sleep-regulatory substances (Krueger et al. 1994). Nuclear factor kappa B (NF-kB) is a heterodimeric transcription factor and is a central regulator of proinflammatory cytokine induction. NF-kB is also activated by the same cytokines that promote sleep. For example, IL-1P, TNF-a (Grilli, Chiu, and Lenardo, 1993), nerve growth factor (Carter, Kaltschmidt, Kaltschmidt, Offenhauser, Bohm-Matthaei, Baeuerle, and Barde, 1996), epidermal growth factor (Obata, Biro, Arima, Kaieda, Kihara, Eto, Miyata, and Tanaka, 1996), and interferon a (Chaturvedi, Higuchi, and Aggarwal, 1994) all activate NF-kB. In contrast, several substances that inhibit sleep, for example, IL-4 (Clarke, Taylor-Fishwick, Hales, Chernajovsky, Sugamura, Feldmann, and Foxwell, 1995), IL-10 (Wang, Wu, Siegel, Egan, and Billah, 1995), glucocorticoids (Unlap and Jope, 1995), directly or indirectly, inhibit NF-kB activation. NF-kB activation promotes production of several additional substances thought to be involved in sleep regulation such as nitric oxide (Oddis and Finkel, 1996). Activation of NF-kB is enhanced by sleep deprivation (Chen, Gardi, Kushikata, Fang, and Krueger 1999). A NF-kB cell-permeable inhibitor peptide injected intracerebroventricularly in rats and rabbits significantly inhibited NREMS and REMS if administered during the light period. Moreover, pretreatment of rabbits with IL-1P 12 h before intracerebroventricular injection of the inhibitor peptide, significantly attenuated IL-ip-induced sleep and febrile responses (Kubota, Kushikata, Fang, and Krueger, 2000). These results suggest that NF-kB activation could be involved in sleep regulation interacted with many sleep-related cytokines.

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