IL-6 and Its Circadian Secretion in Humans

Abstract

Interleukin-6 (IL-6) is a pleiotropic cytokine produced by numerous types of immune and nonimmune cells and is involved in many pathophysiologic mechanisms in humans. Many studies suggest that IL-6 is a putative ‘sleep factor’ and its circadian secretion correlates with sleep/sleepiness. IL-6 is elevated in disorders of excessive daytime sleepiness such as narcolepsy and obstructive sleep apnea. It correlates positively with body mass index and may be a mediator of sleepiness in obesity. Also the secretion of this cytokine is stimulated by total acute or partial short-term sleep loss reflecting the increased sleepiness experienced by sleep-deprived individuals. Studies that evaluated the 24-hour secretory pattern of IL-6 in healthy young adults suggest that IL-6 is secreted in a biphasic circadian pattern with two nadirs at about 08.00 and 21.00, and two zeniths at about 19.00 and 05.00 h. In contrast, following sleep deprivation or in disorders of sleep disturbance, e.g., insomnia, IL-6 peaks during the day and, based on the level of stress system activity, i.e., cortisol secretion, contributes to either sleepiness and deep sleep (low cortisol) or feelings of tiredness and fatigue and poor sleep (high cortisol). In order to address concerns about the potential impact of differences of IL-6 levels between the beginning and the end of the 24-hour blood-drawing experiment, we proceeded with a cosinor analysis of ‘detrended’ data in young and old healthy individuals. This new analysis did not affect the biphasic circadian pattern of IL-6 secretion in young adults, while it augmented the flattened circadian pattern in old individuals in whom the difference was greater. Finally, IL-6 appears to be somnogenic in rats and exhibits a diurnal rhythm that follows the sleep/wake cycle in these animals. We conclude that IL-6 is a mediator of sleepiness and its circadian pattern reflects the homeostatic drive for sleep.

Cortisol response to ACTH stimulation correlates with blood interleukin 6 concentration in healthy humans

“…Therefore, it was proposed that IL6 is involved in the response to somatic stress and in the development of obesity and metabolic syndrome (16,29). In obesity, there is a dissociation between ACTH and cortisol secretion, which is pronounced in the evening, (30) at approximately the same time the second zenith of IL6 concentration occurs (31). Therefore, an IL6 induced increase in cortisol secretion could be a part of the stress response and could be involved in the development of obesity, metabolic syndrome, fatigue and sleep disturbances (16,29).…”

Post-menopausal Women Exhibit Greater Interleukin-6 Responses to Mental Stress Than Older Men

“…Time of testing (morning or afternoon) [9,29] and poststress ruminative thoughts ("I have been thinking about embarrassing moments during the tasks" 1 = not at all to 7 = extremely) [30] were also selected.…”

Genetic and Immunologic Aspects of Sleep and Sleep Disorders

“…For example, increased levels of IL-6 are associated with sleep. 74 IL-6 demonstrates a biphasic pattern, with nadirs at about 8:00 am and 9:00 pm , and it peaks at about 7:00 pm and 5:00 am . Sleep deprivation delays this circadian pattern, such that the increase in IL-6 occurs during the day.…”