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. Author manuscript; available in PMC: 2014 May 22.
Published in final edited form as: Vitam Horm. 2012;89:241–257. doi: 10.1016/B978-0-12-394623-2.00013-5

Humoral Sleep Regulation; Interleukin-1 and Tumor Necrosis Factor

Kathryn A Jewett *,†, James M Krueger *
PMCID: PMC4030541  NIHMSID: NIHMS580567  PMID: 22640617

Abstract

Two substances, the cytokines interleukin-1 beta (IL1β) and tumor necrosis factor alpha (TNFα), known for their many physiological roles, for example, cognition, synaptic plasticity, and immune function, are also well characterized in their actions of sleep regulation. These substances promote non-rapid eye movement sleep and can induce symptoms associated with sleep loss such as sleepiness, fatigue, and poor cognition. IL1β and TNFα are released from glia in response to extracellular ATP. They bind to their receptors on neurons resulting in neuromodulator and neurotransmitter receptor up/downregulation (e.g., adenosine and glutamate receptors) leading to altered neuronal excitability and function, that is, a state change in the local network. Synchronization of state between local networks leads to emergent whole brain oscillations, such as sleep/wake cycles.

I. Introduction

Despite the importance of sleep to our everyday lives, its biochemical regulation continues to confound us. Many studies have provided strong evidence that sleep is regulated, in part, by humoral agents dubbed “sleepregulatory substances” or SRSs (Borbély and Tobler, 1989; Imeri and Opp, 2009; Inoue, 1989; Jouvet, 1984; Kilduff and Peyron, 2000; Krueger, 2008; Krueger et al., 1990, 2008; Obál et al., 2003; Roky et al., 1995). The first discovery of SRSs that accumulated in cerebrospinal fluid during prolonged waking occurred over a century ago (Ishimori, 1909; Legendre and Piéron, 1913).

To be classified as an SRS, a substance must meet several criteria (Borbély and Tobler, 1980; Imeri and Opp, 2009; Jouvet, 1984; Krueger and Obál, 1994). These include (1) the substance and/or its receptor changes with sleep propensity, (2) administration of the substance increases or decreases sleep, (3) blocking the action or inhibiting the production of the substance changes sleep, (4) levels of the substance change during disease states associated with altered sleep, for example, infection, and finally (5) the substance acts on known sleep-regulatory circuits. While there are many substances meeting some of these criteria, including microRNAs, metabolites, hormones, growth factors, transcription factors, and various proteins and their receptors, only a few meet all the required characteristics.

II. Interleukin-1β and Tumor Necrosis Factor α

Two well-characterized SRSs are the cytokines interleukin-1 beta (IL1β) and tumor necrosis factor alpha (TNFα). While well known for their contribution to signaling in the peripheral immune system, cytokines and their receptors are constitutively expressed in the central nervous system of healthy organisms, supporting the notion that they have functions beyond immune responses (Opp, 2005; Szelényi, 2001).

Electrophysiological, biochemical, and molecular genetic studies of IL1β and TNFα demonstrate specific effects on sleep–wake behavior. They seem to promote sleep via similar mechanisms, for example, both activate nuclear factor kappa-B (NF-κB). Many of their downstream biochemical effectors, for example, adenosine, nitric oxide, nerve growth factor, growth hormone-releasing hormone, and prostaglandins, are also implicated in sleep-regulatory roles in health and disease (reviewed in Churchill et al., 2008;Kapsimalis et al., 2005; Krueger et al., 2008). For instance, injection of IL1β or TNFα into humans (mimicking their endogenous accumulation during wakefulness or sleep loss) induces symptoms associated with sleep loss, such as sensitivity to kindling (Yi et al., 2004) and pain stimuli (Honore et al., 2006; Kawasaki et al., 2008; Kundermann et al., 2008), depression (Anisman and Marali, 2003; Vollmer-Conna et al., 2004), sleepiness (Moldofsky, 1995; Obál et al., 2003; Tringall et al., 2000), fatigue (Anisman and Marali, 2003; Carmichael et al., 2006; Omdal and Gunnarsson, 2005), and impairments in cognition (Baune et al., 2008; Gambino et al., 2007; Trompet et al., 2008), memory (Banks and Dinges, 2007; Dantzer, 2004; Pickering and O’Connor, 2007), and performance (Banks and Dinges, 2007). Some of these symptoms can be blocked with the administration of cytokine inhibitors (Depino et al., 2004; Larsen et al., 2007; Opp and Krueger, 1991). Chronic sleep disruption is also associated with multiple pathologies such as metabolic syndrome (Hristova and Aloe, 2006; Jager et al., 2007; Larsen et al., 2007), chronic inflammation (Frey et al., 2007; Hu et al., 2003), and cardiovascular disease (reviewed in Yndestad et al., 2007), and IL1β and TNFα play a role in the etiology of these diseases.

A. Interleukin-1β

IL1β is a somnogenic cytokine originally described as an endogenous pyrogen that induced fever in rabbits (Atkins and Wood, 1955). Immunologists working independently described lymphocyte-activating factor that subsequently was recognized as endogenous pyrogen, and both were given the new name interleukin-1. IL1β is normally produced in response to infection, injury, or immunologic challenge; at minimal concentrations, it causes fever, hypotension, and production of additional proinflammatory cytokines, such as IL6 (Church et al., 2008; Dinarello, 2000). IL1β is a member of the interleukin 1 family that also includes IL1α and IL1 receptor antagonist (IL1ra) (Gibson et al., 2004). The IL1 family now comprises at least 11 different proteins (IL1F1–11) on the basis of their sequence homology, structure, and receptors (Allan et al., 2005; Barksby et al., 2007). IL1β transcription may be induced by proinflammatory stimuli such as microorganisms or their products (Konsman et al., 2002) and by proinflammatory cytokines, including type I interferons (Brandwein, 1986), TNFα (Williams et al., 2000), and IL1β itself (Churchill et al., 2006; Granowitz et al., 1992). Almost all nucleated cells produce IL1β (Brough and Rothwell, 2007). IL1β is produced as a large ~36 kDa (Deak et al., 2005) inactive precursor protein (pro-IL1β) that requires cleavage by caspase-1 (also known as IL1β-converting enzyme) to its active form (a 17 kDa protein) (Barksby et al., 2007; Church et al., 2008; Fogal and Hewett, 2008).

IL1β binds to two receptor subtypes, one of which produces downstream signaling and activation and the other of which lacks an intracellular signaling moiety. Both receptors can also bind IL1ra and IL1α. The receptor that produces activation is an 80 kDa membrane-bound receptor named IL1-receptor (IL1-R) type 1 or IL1-R1 which interacts with the cytoplasmic protein IL1-R accessory protein to form a complex that leads to the recruitment of adaptor molecules (Fitzgerald and O’Neill, 2000). This signaling can lead to the activation of NF-κB and mitogen-activated protein (MAP) Humoral Sleep Regulation; IL1 & TNF 243 kinase (Trinchieri and Sher, 2007). IL1β also can bind to the IL1-R2, a receptor that lacks an intracellular signaling domain, and consequently, no signaling is activated, therefore, the IL1-R2 functions as a decoy receptor (Colotta et al., 1993, 1994). In other words, IL1-R2 binds to IL1β and thereby prevents it from associating with IL1-R1 (Allan et al., 2005). Interestingly, IL1-R1 has a higher binding affinity for IL1ra than for IL1β or IL1α allowing IL1ra to act as a strong antagonist, whereas IL1-R2 has a higher affinity for IL1β than for IL1α supporting an important role for the receptor in regulating IL1 activity (Colotta et al., 1993, 1994; Re et al., 1996).

B. Tumor Necrosis Factor α

TNFα was first discovered as a product of lymphocytes and macrophages, capable of lysing certain cell types, especially tumor cells (Carswell et al., 1975). TNFα is now associated with many physiological functions in both the normal and diseased body (Bertazza and Mocellin, 2008; Bradley, 2008; Perry et al., 2002). TNFα is involved in synaptic scaling, neurogenesis, cognition, immune system coordination, systemic inflammation, and induction of apoptosis. However, like many other cytokines, TNFα has emerged as an important cell-signaling molecule with diverse roles in many tissues, including the brain. In the brain, TNFα is expressed in neurons, microglia, and astrocytes (Breder et al., 1993; Inoue et al., 2000).

TNFα is synthesized as a membrane-bound homotrimer (made up of 26 kDa monomers), pro-TNFα, that is cleaved by the TNFα-converting enzyme (Solomon et al., 1999; Tracey et al., 2008). After cleavage, the soluble cytokine is released as the 17 kDa form which can interact with TNFα cell-surface receptors. Additionally, membrane-bound pro-TNFα can function as a receptor for TNFα antagonists and as a ligand, binding to TNFα cell-surface receptors. Both actions can lead to the suppression of cytokine expression and apoptosis (Tracey et al., 2008).

There are two TNFα cell-surface receptors, TNF-R1 and TNF-R2. The receptors are structurally related, forming trimeric complexes. However, they differ in their affinity for ligands, signaling mechanisms, and cellular expression (TNF-R1 is expressed on virtually all cell types, while TNF-R2 is usually inducible and expressed only in endothelial and immune cells) (Palin et al., 2007; Tracey et al., 2008). Both receptors lack intrinsic enzymatic activity in their intracellular domains and therefore signal by recruitment of cytosolic adaptor proteins via protein–protein interaction domains to activate transcription factors such as NF-κB and members of the MAP kinase pathway (Goeddel, 1999; Ledgerwood et al., 1999). The activation of these transcription factors plays an important role in the induction of many other cytokines and immune-regulatory proteins, in many cases mediating an inflammatory response. In some cases, activation of these transcription factors can induce apoptosis or necrosis (Ledgerwood et al., 1999; Liu, 2005).

III. Cytokine Production and Release

IL1β and TNFα mRNAs are detectable in various areas of the brain in several species (reviewed by Vitkovic et al., 2000). Because constitutive expression of IL1β (Medana et al., 1997; Taishi et al., 1997) and TNFα (Bredow et al., 1997) mRNAs is region specific and diurnal, some studies did not find them in normal rodent brains (reviewed by Vitkovic et al., 2000). IL1β protein is present in many areas in both neurons and glia in normal rat and mouse brains (Bandtlow et al., 1990; Hagan et al., 1993; Lechan et al., 1990; Molenaar et al., 1993; Quan et al., 1998). IL1β is detectable in the normal human cortex in glia but not neurons (da Cunha et al., 1993a,b), although, in mice, neurons express IL1β as determined by immunohistochemistry. Neuronal activity stimulated through activation of transfected channelrhodopsin-2 increases IL1β expression in mouse neurons (Jewett et al., 2011).TNFα protein is found in many areas of the rodent brain (Breder et al., 1993; Ignatowski et al., 1997; Saito et al., 1996). TNFα protein has marked diurnal changes, for example, 10-fold changes in the cortex and hypothalamus, and correlates with mRNA rhythms (Bredow et al., 1997; Floyd and Krueger, 1997). TNFα is found in rat neurons as determined by immunohistochemistry, and like IL1β, expression is activity dependent. Whisker stimulation increases TNFα expression in the correspondingly activated somatosensory cortical columns (Churchill et al., 2008).

Glia synthesize and exocytose a variety of molecules, including IL1β and TNFα, that when injected either systemically or into the brain can increase sleep time or intensity (Halassa et al., 2009; Pascual et al., 2005). For example, IL1β derived from cultured mouse astrocytes increases non-rapid eye movement sleep (NREMS) in rats when administered into the ventricles (Tobler et al., 1984). Astrocytes release IL1β and TNFα in response to neuronal signals, including extracellular ATP acting at purine type 2 (P2) receptors (Bianco et al., 2005; Krueger et al., 2010; Solle et al., 2001; Suzuki et al., 2004; Verderio and Matteoli, 2011). Microglia also synthesize and release cytokines such as IL1β and TNFα in response to extracellular ATP, for example, during ischemia or inflammation (Ferrari et al., 1997; Hide et al., 2000; Inoue, 2002).

IV. Cytokines and Sleep

Cytokines have important roles in multiple physiological functions, including sleep regulation (Krueger et al., 2001), memory (Yirmiya and Goshen, 2011), appetite (Andréasson et al., 2007), cerebral circulation (Faraci and Heistad, 1998), temperature regulation (Leon, 2002), and insulin production (Fu et al., 2006). Several cytokines, including the proinflammatory cytokines IL1α, IL1β, IL6, IFNα, IFNγ, TNFα, and TNFβ, have the capacity to enhance NREMS (reviewed by Krueger and Majde, 2003; Krueger et al., 2001). Two cytokines studied extensively for their relationship with sleep are IL1β and TNFα (Opp, 2005). Endogenous production of IL1β and TNFα and conditions that enhance their production, for example, excessive food intake (Hansen et al., 1998) or infectious disease (Toth and Krueger, 1988), promote NREMS (Krueger et al., 2007; Obál and Krueger, 2003). IL1β and TNFα are constitutively expressed in the brain. In rats, IL1β and TNFα mRNA and protein levels exhibit a diurnal variation in certain areas of the brain, with higher concentrations correlating with higher sleep propensity (Bredow et al., 1997; Taishi et al., 1997). Furthermore, after sleep deprivation, increases in NREMS as well as increases in IL1β and TNFα expression in the brain occur (Krueger et al., 2001; Taishi et al., 1998; Takahashi et al., 1997).

The sleep-promoting actions of IL1β were initially demonstrated in rabbits. Central administration of IL1β enhances NREMS in this species (Krueger et al., 1983, 1984). Further, intracerebroventricular (ICV) injection with an IL1-R1 fragment, an IL1β inhibitor, reduces sleep (Takahashi et al., 1999). In rats, enhanced NREMS occurs after ICV injection of low doses of IL1β (Opp et al., 1991). In contrast, anti-IL1 antibodies or IL1ra reduce spontaneous sleep and inhibit sleep rebound after sleep deprivation (Obál, et al., 1990). Mice display a robust increase in NREMS and suppressed rapid eye movement sleep (REMS) after intraperitoneal injection with IL1β. These effects are abolished IL1-R1 knockout mice; the knockout mice also have less spontaneous sleep than corresponding controls (Fang et al., 1998). Exogenous administration of IL1β also increases NREMS in other species such as cats (Susić and Totić, 1989), monkeys (Friedman et al., 1995), and humans (Dinarello, 1991). In humans, plasma IL1β peaks at slow-wave sleep onset (Moldofsky et al., 1986). The firing rate of hypothalamic sleep-active neurons is enhanced by IL1β; it inhibits wake-active neurons (Alam et al., 2004). IL1β injected into the locus coeruleus (De Sarro et al., 1997) or the dorsal raphe nuclei (Manfridi et al., 2003) promotes NREMS. These results suggest a role for IL1β in the regulation of physiological sleep (Krueger, 2008).

The somnogenic effects of TNFα were first described after ICV injection of recombinant TNFα into rabbits (Shoham et al., 1987). Intravenous or ICV administration of exogenous TNFα enhances the duration and intensity of NREMS and decreases REMS in this species (Kapás and Krueger, 1992; Shoham et al., 1987). The use of anti-TNFα antibodies or the TNF-soluble receptor attenuates spontaneous sleep and reduces sleep rebound after sleep deprivation (Krueger et al., 2001; Takahashi et al., 1995, 1996). In rats, peripheral administration of TNFα increases NREMS (Kubota et al., 2001). Unilateral microinjection of TNFα into the preoptic area of the anterior hypothalamus or the locus coeruleus increases NREMS in a dose-dependent manner (De Sarro et al., 1997; Kubota et al., 2002; Terao et al., 1998). After intraperitoneal injection of TNFα, mice show a dose-dependent increase in NREMS. This effect is not observed in TNF-R1 knockout mice; they also have significantly less baseline NREMS and REMS than controls (Fang et al., 1997). Finally, in sheep, ICV injection of TNFα results in an increase in NREMS (Dickstein et al., 1999). These results suggest that TNFα also has a role in the regulation of physiological sleep (Krueger and Majde, 2003).

The sleep-regulatory roles of IL1β and TNFα are closely related to each other (Baracchi and Opp, 2008). For example, IL1-R1/TNF-R1 double knockout mice have a reduced NREMS rebound (compared with wild type) and do not exhibit an REMS rebound in response to sleep deprivation (Baracchi and Opp, 2008). Furthermore, in TNF-R1 knockout mice that are nonresponsive to TNFα, whereas an injection of IL1β increases NREMS in these mice (Fang et al., 1997). Similarly, the IL1-R1 knockout mice show increased NREMS and decreased REMS after administration of TNFα (Fang et al., 1998).

In addition to increasing time spent sleeping, central injection of IL1β and TNFα can enhance electroencephalographic (EEG) delta (0.5–4 Hz) power (a measure of sleep intensity), also known as slow-wave activity (SWA), during NREMS but not during REMS or waking. Enhanced SWA is also seen after sleep deprivation (Borbély and Tobler, 1989; Pappenheimer et al., 1975), suggesting that IL1β and TNFα injections mimic the effects of sleep loss.

V. Cytokines in Sleep Regulation

The dominant paradigm in sleep research posits that sleep is initiated and regulated by subcortical neuronal networks (reviewed in Szymusiak and McGinty, 2008).

The arousal systems, for example, the noradrenergic locus coeruleus, serotonergic dorsal raphe nucleus, cholinergic neurons in the basal forebrain, and histaminergic neurons in the tuberomammillary nucleus, provide activating inputs to the diencephalon, limbic system, and neocortex (Saper, 1987). The hypocretin (orexin) neurons in the perifornical region of the lateral hypothalamus constitute another functionally important arousal regulatory cell group (Peyron et al., 1998). GABAergic neurons with enhanced activity during and just prior to sleep are found in the ventrolateral preoptic area of anterior hypothalamus (Sherin et al., 1996, 1998; Szymusiak et al., 1998). These neurons are posited to impose sleep on the rest of the brain by their inhibition of the various arousal/activating systems (reviewed by Saper et al., 2005).

There are many well-known phenomena that cannot be explained by the top-down sleep-regulatory center-imposed sleep paradigm. The most substantial evidence against a necessary top-down sleep-regulatory mechanism comes from lesion studies; if an animal or human survives a brain lesion (e.g., stroke) in any location, it will sleep. There are no reported cases of a complete loss of sleep, including in patients with fatal familial insomnia (Montagna, 2005). The top-down paradigm has little explanatory value for sleep homeostatic mechanisms or how performance is restored during sleep. The existence of parasomnias, such as sleepwalking, indicates that areas of the brain can be awake while other areas are asleep (Mahowald and Schenck, 2005). Many species of birds and marine mammals exhibit unihemispheric sleep (Lyamin et al., 2002, 2008; Rattenborg et al., 2001). Finally, isolated cortical islands retaining their blood flow but no afferent projections show periods of high-amplitude delta waves measured from the cortical surface (Kristiansen and Courtois, 1949).

Such considerations led to the theory that sleep is a local use-dependent phenomenon. The functional states (i.e., asleep or awake) of different parts of the brain can vary. For example, dolphins do not exhibit high-amplitude EEG slow waves simultaneously in both cerebral hemispheres (Mukhametov et al., 1977). During a visual discrimination task, when a monkey becomes drowsy, but is still behaving, some neurons in the cortical visual receptive fields exhibit the burst-pause sleep-like pattern before others as the animal enters sleep (Pigarev et al., 1997). Which neurons switch to the burst-pause pattern depends on their topographic location within their receptive field, indicating that the transition from wake to sleep is a local network phenomenon. Similarly, using surface-evoked response potentials to characterize cortical column state, Rector et al. (2005) demonstrated that individual columns semiautonomously oscillate between sleep- and wake-like states. The duration of the localized sleep-like state of a cortical column is dependent on its prior wake-like state duration, suggesting that the local functional state of the column is use-dependent and homeostatic (Rector et al., 2009).

Other studies also suggest the use-dependent regulation of local sleep. For example, during the first NREMS episode after a hand is stimulated prior to sleep by vibration, the EEG SWA is enhanced in the somatosensory cortex contralateral to the stimulated hand as compared to the ipsilateral side (Kattler et al., 1994). Cerebral blood flow during sleep is increased in areas which are disproportionately stimulated during prior waking (Maquet, 2001). The neuronal electrical firing in the cortex and hippocampus during sleep replays the activation pattern learned during a waking task (Ji and Wilson, 2007). After a special motor-learning task just prior to sleep, the cortical area activated by this learning task has enhanced subsequent EEG SWA as compared to the unstimulated regions (Huber et al., 2004).

The use-dependent regulation of sleep is, at least in part, mediated by the SRSs that are produced and released locally in response to the neuronal and glial activity during wakefulness. For instance, in rats, stimulation of whiskers leads to increased expression of TNFα in the corresponding cortical columns (Churchill et al., 2008). When TNFα is applied directly to the cortex unilaterally, EEG SWA is enhanced on the side of injection (Yoshida et al., 2004), and the sleep-like state of the underlying cortical column is increased (Churchill et al., 2008). In addition, unilateral application of a TNFα small-interfering RNA to the cortex inhibits local EEG SWA and neuronal TNFα expression (Taishi et al., 2007). Collectively, these experiments suggest that the production of SRSs depends on the prior activity of the cortical columns, and the functional states of cortical columns are affected by the SRSs. These studies support the theory that sleep is initiated at a local network level in the circuits most active during prior waking. Whole organism sleep is posited to emerge with the synchronization of local network state changes orchestrated in part by the known sleep-regulatory circuits (Krueger et al., 2008; Roy et al., 2008).

A mechanism linking cellular activity to sleep is based on extracellular adenosine triphosphate (ATP) and cytokines. ATP is released into the extracellular space during neuro and gliotransmission (reviewed in Burnstock, 2006, 2007; Halassa et al., 2009). Extracellular ATP induces the release of SRSs like IL1β and TNFα from glia via P2 receptors (reviewed by Bianco et al., 2005; Hide et al., 2000; Krueger et al., 2010; Solle et al., 2001; Suzuki et al., 2004; Verderio and Matteoli, 2011). Thus local levels of SRSs reflect prior local network activity. These substances can then bind to receptors of nearby neurons, directly altering electrical activity (fast process) and altering gene transcription and translation (slow process), leading to changes in receptor populations such as AMPA and adenosine receptors (reviewed by Obál and Krueger, 2003). Extracellular ATP can also be hydrolyzed by ectonucleotidases releasing extracellular adenosine that in turn acts on adenosine receptors (Fields and Stevens, 2000). All these processes can alter the responsiveness of neurons and their input–output relationships, leading to state changes and ultimately sleep.

ACKNOWLEDGMENT

This work was supported by grants from the National Institutes of Health, NS025378, NS031453, and HD36520.

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