The Role of Cytokines in Sleep Regulation

Abstract

Interleukin-1 beta (IL1) and tumor necrosis factor alpha (TNF) promote non-rapid eye movement sleep under physiological and inflammatory conditions. Additional cytokines are also likely involved but evidence is insufficient to conclude that they are sleep regulatory substances. Many of the symptoms induced by sleep loss, e.g. sleepiness, fatigue, poor cognition, enhanced sensitivity to pain, can be elicited by injection of exogenous IL1 or TNF. We propose that ATP, released during neurotransmission, acting via purine P2 receptors on glia releases IL1 and TNF. This mechanism may provide the means by which the brain keeps track of prior usage history. IL1 and TNF in turn act on neurons to change their intrinsic properties and thereby change input-output properties (i.e. state shift) of the local network involved. Direct evidence indicates that cortical columns oscillate between states, one of which shares properties with organism sleep. We conclude that sleep is a local use-dependent process influenced by cytokines and their effector molecules such as nitric oxide, prostaglandins and adenosine.

Depression in Autoimmune Diseases

“…It is well established that rodents injected systemically or intacerebroventricularly with cytokines including TNF and IL-1 show an increase in sleep at times when mice are usually active (for review see (Imeri and Opp, 2009;Krueger, 2008)). NREM sleep was found to be increased in the …”

Biochemical Regulation of Sleep and Sleep Biomarkers

“…3,4 It is thus an attractive idea that one or more of these molecules, or the downstream changes in molecular events induced by these molecules, could serve as an index to sleepiness and prior time awake, predict how long someone may sleep if allowed, correlate with an individual's performance status, or be useful in the diagnosis of primary sleep disorders. Herein, we conclude that the simultaneous determination of several of such molecules may indeed be useful for these purposes.…”

“…4,9,10 These include: 1) the substance and/or its receptor oscillates with sleep propensity; 2) sleep is increased or decreased with administration of the substance; 3) blocking the action or inhibiting the production of the substance changes sleep; 4) disease states, e.g., infection, associated with altered sleep also change levels of the putative SRS; and finally 5) the substance acts on known sleep regulatory circuits. While many substances meet 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 to be considered an SRS.…”

“…4 For instance, injection of antibodies to these cytokines, their soluble receptors, or small interfering RNA (siRNA) targeting IL1 or TNF reduces NREMS and/or EEG δ power, e.g. Taishi et al 31 Mice lacking the TNF55kD receptor, 32 or the type 1 IL1 receptor, 33 or both TNF receptors 34 sleep less than control mice.…”

“…Taishi et al 31 Mice lacking the TNF55kD receptor, 32 or the type 1 IL1 receptor, 33 or both TNF receptors 34 sleep less than control mice. Some endogenous molecules inhibit IL1 and TNF and also attenuate spontaneous NREMS including IL-4, IL-10, IL-13, 3 corticotrophin releasing hormone, 35 IL1-receptor antagonist, 4 and others (see Figure 1). We have recently found that transgenic mice with the ability to express human IL-37b, a suppressor of multiple pro-somnogenic cytokines 36 sleep less after sleep deprivation than under baseline conditions.…”