The influence of cytokines on wakefulness regulation: clinical relevance, mechanisms and methodological problems

Sleep-wake-regulation has been shown to be substantially influenced by cytokines. The clinical relevance of this issue arises from (1) the frequency of accidents, injuries and impairment in social functioning due to sleepiness, (2) the occurrence of fatigue syndromes associated with inflammatory diseases, cancer or obesity, (3) the role of wakefulness regulation for the pathophysiology of affective and sleep disorders and (4) sedation as a side effect of psychopharmacological therapy. Experimental studies confirm the somnogenic influence of pro-inflammatory cytokines such as interleukin (IL)-1β, IL-6 and tumor necrosis factor-α (TNF-α). These cytokines modulate centers of wakefulness regulation located in the hypothalamus, the basal forebrain and the brain stem by influencing substances involved in sleep-wake-behavior such as adenosine, nitric oxide (NO), nuclear factor-κB (NF-κB), prostaglandin D2 (PGD2), the neurotransmitters γ-aminobutyric acid (GABA), glutamate and norepinephrine, as well as hormones such as growth hormone-releasing hormone (GHRH) and corticotropin-releasing hormone (CRH). Clinical studies of the influence of cytokines on wakefulness regulation are underrepresented in the research literature and objective measures of wakefulness such as the Multiple Sleep Latency Test (MSLT) are seldom reported.