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.

Fig. (1)

Many biological variables are associated with sleep patterns. The interveining hormonal and humoral substances acting to affect sleep are known in many cases; such substances act over different time lines to alter expressions of sleep phenotypes. Abbreviations: CRH, corticotropin releasing hormone; GHRH, growth hormone releasing hormone; PGD₂, prostaglandin D₂; VIP, vasoactive intestinal polypeptide; TNF, tumor necrosis factor alpha; CCK, cholecystokinin; NPY, neuro-peptide Y; GABA, gamma amino butyric acid; NO, nitric oxide.

Fig. (2)

Cytokines such as IL1, TNF, nerve growth factor (NGF), EGF, interleukin 4 (IL4), interleukin 10 (IL10), and associated soluble and membrane-bound receptors all form part of the sleep biochemical regulatory network. Cell activity affects levels of these substances. Within brain for example, ATP, co-released during neurotransmission, induces the release of the gliotransmitters IL1 and TNF from glia. These substances induce their own production and interact with multiple other substances via NFkB activation. These effects are associated with gene transcription and translation and take several hours. Downstream events include well-known metabolic substances and regulators of the microcirculation such as NO, adenosine and prostaglandins. Neurotransmission, acting on an even faster time scale, is altered by substances such as IL1 via actions on the production of receptors that alter postsynaptic neuron sensitivity such as AMPA and adenosine A1 receptors (A1AR). State oscillations within local networks occur as a result of this ultra-complex biochemical regulatory scheme [2,3,56]. Abbreviations:P2, purine type 2 receptors; NFkB, nuclear factor kappa B; NOS, nitric oxide synthase; NGF, nerve growth factor; EGF, epidermal growth factor; GHRH, growth hormone releasing hormone; CRH, corticotrophin releasing hormone; IL1RA, IL1 receptor antagonist; sIL1R, soluble IL1 receptor; sTNFR, soluble TNF receptor; PGs, prostaglandins; COX, cyclooxygenase; glu, glutamic acid; GABA, gamma amino butyric acid; CRH, corticotrophin releasing hormone; sTNFR, soluble TNF receptor;, sIL1R, soluble IL1 receptor; TGF, transforming growth factor beta; cry, cryptochrome; per, period.

Fig. (3)

Application of tumor necrosis factor alpha (TNF) unilaterally (left) to the somatosensory cortex enhances EEG delta power on the ipsilateral side during NREMS. Such responses occur during NREMS but not during REMS or waking (modified from 86].

Fig. (4)

Neuronal activity is linked via ATP released during neurotransmission to both long-term and short-term mechanisms involved in neuronal assembly state and in events involved in synaptic scaling.