Elsevier

Sleep Medicine Reviews

Volume 40, August 2018, Pages 69-78
Sleep Medicine Reviews

Physiological Review
Tumor necrosis factor alpha in sleep regulation

https://doi.org/10.1016/j.smrv.2017.10.005Get rights and content

Summary

This review details tumor necrosis factor alpha (TNF) biology and its role in sleep, and describes how TNF medications influence sleep/wake activity. Substantial evidence from healthy young animals indicates acute enhancement or inhibition of endogenous brain TNF respectively promotes and inhibits sleep. In contrast, the role of TNF in sleep in most human studies involves pathological conditions associated with chronic elevations of systemic TNF and disrupted sleep. Normalization of TNF levels in such patients improves sleep. A few studies involving normal healthy humans and their TNF levels and sleep are consistent with the animal studies but are necessarily more limited in scope. TNF can act on established sleep regulatory circuits to promote sleep and on the cortex within small networks, such as cortical columns, to induce sleep-like states. TNF affects multiple synaptic functions, e.g., its role in synaptic scaling is firmly established. The TNF-plasticity actions, like its role in sleep, can be local network events suggesting that sleep and plasticity share biochemical regulatory mechanisms and thus may be inseparable from each other. We conclude that TNF is involved in sleep regulation acting within an extensive tightly orchestrated biochemical network to niche-adapt sleep in health and disease.

Introduction

Sleep remains a fundamental scientific enigma. Although significant progress has been made in elucidating roles for sleep in cognition and brain health, the primary functions of sleep have not been firmly established. Moreover, the regulation of sleep and wake is complex and not fully understood, and newer questions have arisen regarding the role and need for local sleep within a specific brain region versus more generalized sleep states. We do, however, appreciate that sleep manifestations are systemic. Sleep affects almost every physiological function, e.g., body temperature, hormone secretions, and respiratory, cardiac, kidney, and immune functions. Sleep actions on the brain range from altering multiple pathologies to recovery from them, as well as performance, mentation, emotion, learning and memory, etc. At the same time, many physiological functions affect sleep, e.g., body temperature, hunger, sexual drive, development, respiration, etc. and extracellular signals involved in the regulation of these functions affect sleep [1]. This latter point is critical to appreciate, as these physiological effects are not accounted for within the two-process (homeostasis and circadian) regulation of sleep model [2]. Fig. 1 illustrates some of the known components of tumor necrosis factor alpha (TNF) regulation and TNF biological activities that are also linked to sleep. Although the biochemical network shown is incomplete, it and the more extensive network (not shown) are likely beyond the capacity of any individual's ability to fully understand the dynamic nuances of such networks. Further, how the components interact with other TNF-regulated processes to orchestrate sleep niche adaptation further challenges comprehension. Herein we focus on only one sleep regulatory substance, TNF. We do so in recognition that other molecules are also involved in sleep regulation, but focus on TNF to illustrate principles of physiological sleep regulation and function. The reader is referred to other reviews for broader treatments of sleep regulation, both biochemical [3], [4], [5], [6], ∗[7], [8], [9], neurobiological [10], [11], and glialogical [12], [13], [14], [15].

Section snippets

TNF biology

Within the brain, TNF has many functions including mediation of brain damage, e.g., cerebral ischemia [17], cerebral blood flow, neuro-protection, responses to infection, and synaptic scaling [18]. TNF is expressed by microglia, astrocytes, and neurons [19], [20], [21], [22]. The actions of TNF depend not only on the receptor type – either 55 kilo-Daltons (kD) or 75 kD – and adaptor proteins, but also on the context of the stimulus and the interaction with substances that modify TNF activity.

TNF in sleep regulation; animal studies

A sleep regulatory substance should be able to satisfy several basic criteria [50], [51], [52]. In animal studies, a sleep regulatory substance should enhance a sleep phenotype, such as duration of non-rapid eye movement sleep (NREMS). Inhibition or reduction of the substance should reduce the sleep phenotype. The levels of the purported sleep regulatory substance measured in the brain should correlate with the duration of sleep loss and sleep propensity. Additionally, the sleep regulatory

Linking TNF to human sleep

TNF blood levels correlate with EEG δ power during spontaneous sleep in humans [79]. During sleep in healthy young men, serum TNF levels decrease [80]; this finding is consistent with the reduction of brain TNF across the rat daytime sleep period [64]. After sleep deprivation in humans, circulating levels of the 55 kD soluble TNFR, but not the 75 kD soluble TNFR, increase [81], ∗[82]. The soluble 55 kD R is a component of normal cerebrospinal fluid [83]. The TNF system may play a role in normal

Etanercept (ETA)

ETA is a recombinant TNFR protein that binds TNF thereby reducing the effects of naturally present TNF [102]. It is not known if ETA can bind to the 26 kD trans-membrane form of TNF to reverse signal (see above), thus interpretation of clinical studies is speculative. Nevertheless, because TNF is a key inflammatory regulator, ETA is used to treat autoimmune diseases [103]. ETA was the first FDA approved medicine for rheumatoid arthritis and polyarticular-course juvenile rheumatoid arthritis

TNF sleep biology within the context of brain organization of sleep

Despite millions of human stroke cases and many animal brain lesion studies, if the subject survived, sleep always ensues. Although post-lesion sleep may not have normal structure with oscillations between NREMS and REMS and periodic awaking, sometimes duration of sleep recovers [141], [142], [143]. This strongly suggests that no specific circuit is required for sleep and that sleep has self-organizing properties in any viable brain tissue that remains after lesions. Further, several marine

Conclusion

There is ample evidence from animals and humans that TNF is involved in sleep regulation. TNF biology and TNF sleep mechanisms reveal much about sleep regulation, the minimal amount of tissue required for sleep, and sleep function. Local application of TNF to small circuits, such as cortical columns or to co-cultures of neurons and glia induces sleep-like states. The in vivo and in vitro sleep-like states suggest that sleep is a fundamental property of very small circuits. TNF is expressed in

Conflicts of interest

The authors do not have any conflicts of interest to disclose.

Acknowledgements

This work was supported by grants to JMK from The National Institutes of Health (USA), grant numbers NS025378, NS096250 and HD36520 and HL123331 to both JMK and SCV.

References (158)

  • R. Yirmiya et al.

    Immune modulation of learning, memory, neural plasticity and neurogenesis

    Brain Behav Immun

    (2011)
  • M. Kriegler et al.

    A novel form of TNF/cachectin is a cell surface cytotoxic transmembrane protein: ramifications for the complex physiology of TNF

    Cell

    (1988)
  • D.V. Goeddel

    Signal transduction by tumor necrosis factor: the Parker B. Francis Lectureship

    Chest

    (1999)
  • J. Inoue et al.

    Tumor necrosis factor receptor-associated factor (TRAF) family: adapter proteins that mediate cytokine signaling

    Exp Cell Res

    (2000)
  • L. Churchill et al.

    Tumor necrosis factor alpha: activity dependent expression and promotion of cortical column sleep in rats

    Neuroscience

    (2008)
  • S.E. Borst et al.

    High-fat diet induces increased tissue expression of TNF-alpha

    Life Sci

    (2005)
  • A. De et al.

    Tumor necrosis factor alpha increases cytosolic calcium responses to AMPA and KCl in primary cultures of rat hippocampal neurons

    Brain Res

    (2003)
  • M. Karrer et al.

    Cytokine-induced sleep: neurons respond to TNF with production of chemokines and increased expression of Homer1a in vitro

    Brain Behav Immun

    (2015)
  • S.E. Nelson et al.

    Homer1a and 1bc levels in the rat somatosensory cortex vary with the time of day and sleep loss

    Neurosci Lett

    (2004)
  • S. Takahashi et al.

    An anti-tumor necrosis factor antibody suppresses sleep in rats and rabbits

    Brain Res

    (1995)
  • D.P. Venancio et al.

    Prolonged REM sleep restriction induces metabolic syndrome-related changes: mediation by pro-inflammatory cytokines

    Brain Behav Immun

    (2015)
  • N.T. Ashley et al.

    Novel environment influences the effect of paradoxical sleep deprivation upon brain and peripheral cytokine gene expression

    Neurosci Lett

    (2016)
  • F. Cathomas et al.

    CD40-TNF activation in mice induces extended sickness behavior syndrome co-incident with but not dependent on activation of the kynurenine pathway

    Brain Behav Immun

    (2015)
  • T. Kubota et al.

    Intrapreoptic microinjection of TNF-α enhances non-REM sleep in rats

    Brain Res

    (2002)
  • G. De Sarro et al.

    Comparative, behavioural and electrocortical effects of tumor necrosis factor-α and interleukin-1 microinjected into the locus coeruleus of rat

    Life Sci

    (1997)
  • H. Yoshida et al.

    State-specific asymmetries in EEG slow wave activity induced by local application of TNFα

    Brain Res

    (2004)
  • P. Taishi et al.

    TNFα siRNA reduces brain TNF and EEG delta wave activity in rats

    Brain Res

    (2007)
  • S. Dimitrov et al.

    Differential acute effects of sleep on spontaneous and stimulated production of tumor necrosis factor in men

    Brain Behav Immun

    (2015)
  • W.T. Shearer et al.

    Soluble TNF-alpha receptor 1 and IL-6 plasma levels in humans subjected to the sleep deprivation model of spaceflight

    J Allergy Clin Immunol

    (2001)
  • M. Haack et al.

    Diurnal and sleep-wake dependent variations of soluble TNF- and IL-2 receptors in healthy volunteers

    Brain Behav Immun

    (2004)
  • A. Khalyfa et al.

    TNF-α gene polymorphisms and excessive daytime sleepiness in pediatric obstructive sleep apnea

    J Pediatr

    (2011)
  • P. Bielicki et al.

    Cytokine gene polymorphisms inobstructive sleep apnoea/hypopnoea syndrome

    Sleep Med

    (2015)
  • C.J. Davis et al.

    Sleep and cytokines

    Sleep Med Clin

    (2012)
  • E. Ceylan et al.

    Evaluation of TNF-alpha gene (G308A) and MBL2 gene codon 54 polymorphisms in Turkish patients with tuberculosis

    J Infect Public Health

    (2017)
  • B.C. Satterfield et al.

    TNFalpha G308A polymorphism is associated with resilience to sleep deprivation-induced psychomotor vigilance performance impairment in healthy young adults

    Brain Behav Immun

    (2015)
  • M.R. Opp et al.

    Sleep fragmentation and sepsis differentially impact blood–brain barrier integrity and transport of tumor necrosis factor-α in aging

    Brain Behav Immun

    (2015)
  • F. Obal et al.

    Humoral mechanisms of sleep

  • A.A. Borbely

    Processes underlying sleep regulation

    Horm Res

    (1998)
  • Z.L. Huang et al.

    The role of adenosine in the regulation of sleep

    Curr Top Med Chem

    (2011)
  • O. Arias-Carrion et al.

    Biochemical modulation of the sleep-wake cycle: endogenous sleep-inducing factors

    J Neurosci Res

    (2011)
  • S. Sheth et al.

    Adenosine receptors: expression, function and regulation

    Int J Mol Sci

    (2014)
  • J.M. Krueger et al.

    Sleep: a synchrony of cell activity-driven small network states

    Eur J Neurosci

    (2013)
  • J.M. Krueger et al.

    Sleep as a fundamental property of neuronal assemblies

    Nat Rev Neurosci

    (2008)
  • P.H. Luppi

    Neurochemical aspects of sleep regulation with specific focus on slow-wave sleep

    World J Biol Psychiatry

    (2010)
  • R. Szymusiak et al.

    Hypothalamic regulation of sleep and arousal

    Ann N Y Acad Sci

    (2008)
  • J. O'Donnell et al.

    Distinct functional states of astrocytes during sleep and wakefulness: is norepinephrine the master regulator?

    Curr Sleep Med Rep

    (2015)
  • M. Guo et al.

    Preischemic induction of TNF-alpha by physical exercise reduces blood-brain barrier dysfunction in stroke

    J Cereb Blood Flow Metab

    (2008)
  • C.D. Breder et al.

    Distribution and characterization of tumor necrosis factor-alpha-like immunoreactivity in the murine central nervous system

    J Comp Neurol

    (1993)
  • G.I. Botchkina et al.

    Expression of TNF and TNF receptors (p55 and p75) in the rat brain after focal cerebral ischemia

    Mol Med

    (1997)
  • M. Shibata

    Hypothalamic neuronal responses to cytokines

    Yale J Biol Med

    (1990)
  • Cited by (82)

    View all citing articles on Scopus
    1

    Equal contributions by Rockstrom and Chen as first author.

    The most important references are denoted by an asterisk.

    View full text