Sleep, the hypothalamic-pituitary-adrenal axis, and cytokines: multiple interactions and disturbances in sleep disorders

Sleep is an important component of mammalian homeostasis, vital for our survival. Sleep disorders are common in the general population and are associated with significant medical, psychologic, and social disturbances. Sleep, in particular deep sleep, has an inhibiting influence on the hypothalamic-pituitary-adrenal (HPA) axis, whereas activation of the HPA axis or administration of glucocorticoids can lead to arousal and sleeplessness. Insomnia, the most common sleep disorder, is associated with a 24-hour increase of corticotropin and cortisol secretion, consistent with a disorder of central nervous system hyperarousal. Sleepiness and fatigue are very prevalent in the general population, and recent studies have demonstrated that the proinflammatory cytokines interleukin-6 (IL-6) or tumor necrosis factor-alpha (TNF-alpha) are elevated in disorders associated with excessive daytime sleepiness, such as sleep apnea, narcolepsy, and idiopathic hypersomnia. Sleep deprivation leads to sleepiness and daytime hypersecretion of IL-6. Combined, these findings suggest that the HPA axis stimulates arousal whereas IL-6 and TNF-alpha are possible mediators of excessive daytime sleepiness in humans.