Physiological ReviewCytokines and sleep☆
Introduction
Cytokines are ancient molecules. They have been sequenced from vertebrates extending back to jawless fish, which evolved at least 500 million years ago.1 Invertebrate host defense systems also include cytokine-related molecules, including interleukin (IL)-1-, IL-6- and tumor necrosis factor-like molecules [see (2) for review]. These cytokine-like molecules and their receptors occur in invertebrates of both protostome and deuterostome branches of the animal kingdom, often in neural cells. Protostomes and deuterostomes arose from monophyletic origins with the bifurcation in the animal kingdom occurring some 850 million years ago. The fact that cytokines or cytokine-like molecules exist in both major phyletic branches of the animal kingdom with bifurcation from common ancestors at least 850 million years ago raises the possibility that early precursors of these molecules may have served functions in addition to host defense. Phylogenetic evidence supports the idea that even cytokines of recent origin may have originally evolved to serve functions other than signaling in the peripheral immune system. For example, one subclass of chemokines (chemoattractant cytokines), the CXC chemokines, evolved exclusively in mammals and although these chemokines serve many immune-related functions their ancestral forms originated within the central nervous system, not the peripheral immune system.3
If indeed cytokines evolved to serve functions other than, or in addition to, signaling within the immune system, then evidence for such actions should exist today. Cytokines have generally been discovered and characterized as components of the peripheral immune system. Although far from fully understood, the role of cytokines as immunomodulators in the peripheral immune system is well documented. As such, evidence of a non-immune function for cytokines must be obtained in the absence of immune challenge. Studies of interactions between cytokine systems and sleep–wake behavior provide such evidence. That several cytokines and their receptors are constitutively expressed in the central nervous system of healthy organisms also supports the notion that cytokines may have originally evolved for functions other than signaling in the peripheral immune system. This article will review the extant literature on cytokines and sleep from this perspective; data demonstrate that at least two cytokines are involved in the regulation of sleep during health and thus function in a context other than during immune activation.
One of the conceptual considerations necessary to facilitate interpretation of extant data on cytokines and sleep are the criteria by which molecules may be said to regulate sleep–wake behavior. A dichotomy in the literature on the regulation of sleep exists because of the historical context within which the field evolved and the tools used for investigation. Methods used to elucidate sleep regulatory mechanisms have historically been broadly divided into electrophysiology and biochemistry. The tools used by practitioners of these methods have strengths and weaknesses, and as with any scientific method there are limitations to conclusions that may be drawn. Electrophysiologists wish to know the impact of a particular manipulation or substance on membrane properties or neuronal discharge patterns, particularly in brain regions and nuclei that have been implicated in the regulation of arousal state. Biochemists wish to know how a particular substance interacts with receptors to induce changes in behavior. Such a generalized dichotomy is of course artificial; communication among most neurons requires action potentials to release transmitter substances into synaptic clefts where they may then bind to receptors on postsynaptic neurons. With respect to the regulation of sleep, several brain regions have been identified in which changes in neuronal discharge patterns are associated with changes in behavioral state, and in which biochemical manipulations alter sleep–wake behavior. Examples include, but are not limited to the preoptic area of the hypothalamus and the basal forebrain, as well as several brain stem nuclei [reviewed in 4, 5]. Recent technologic advances have led to the increasing use of molecular genetic approaches to further elucidate sleep-regulatory mechanisms. As with earlier methods used by electrophysiologists and biochemists, there are strengths and weaknesses associated with the use of molecular genetic approaches to the study of arousal state. Two cytokines, interleukin-1 (IL-1) and tumor necrosis factor (TNF), have been studied to such an extent that data with respect to sleep–wake behavior exist from electrophysiological, biochemical, and molecular genetic studies; these data support a role in the regulation of sleep under physiologic conditions. As such, in this review IL-1 and TNF are referred to as sleep regulatory cytokines. Many other cytokines have been studied to determine a potential role in sleep regulation. For most of these other cytokines (see later) there is limited information as to the extent, and under what conditions, they are capable of altering arousal state. Although plausible mechanisms have been postulated whereby several of these cytokines may alter arousal state, little information actually exists with respect to mechanisms responsible for the manifestation of actions on arousal state. In fact, most of the studies of this group of cytokines have been limited to administration of the cytokine, with no attempts to target systems for intervention or to manipulate their genes/gene products. As such, most cytokines studied to date may be said to be sleep modulatory solely on the basis of their ability to alter sleep–wake behavior when administered to experimental subjects.
Section snippets
Sleep regulatory cytokines
Much data demonstrate that at least two cytokines, IL-1β (hereafter referred to as IL-1) and TNFα (hereafter referred to as TNF) are involved in the regulation of sleep. These two cytokines may be considered as sleep regulatory because data derived from electrophysiological, biochemical and molecular genetic studies demonstrate specific effects on sleep–wake behavior. Furthermore, electrophysiological, biochemical and molecular responses to alterations in the activities of these cytokine
Sleep modulatory cytokines
The impact of many immunomodulators on sleep–wake behavior has been determined in the 20 years since IL-1 was reported to induce alterations in sleep. Although most immunomodulators studied have been cytokines, some chemokines and growth factors have also been investigated in this respect. Collectively, the list of these immunomodulators is quite impressive and includes cytokines and chemokines such as TNFβ, IL-1α, IL-2, IL-4, IL-6, IL-8, IL-10, IL-13, IL-15, IL-18, interferon (IFN)α/β, IFNγ,
Functional significance
Data reviewed herein indicate cytokines regulate and/or modulate sleep–wake behavior in the absence of immune challenge. The data implicating IL-1 and TNF in the regulation of sleep–wake behavior are as extensive, or more so, than those data demonstrating a role for other putative sleep factors, such as adenosine [reviewed (18)]. The IL-1, TNF, IL-6 and/or IFN systems are dramatically upregulated in response to immune challenge. In addition to IL-1, TNF, IL-6 and/or IFN, each of the other
Acknowledgements
The author was supported by National Institutes of Health grant MH64843 and the Department of Anesthesiology of the University of Michigan Medical School while writing this review.*
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This paper is dedicated to the memory of Ferenc Obál, Jr.