Cytokines and Sleep Regulation During Illness

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Cytokines are proteins that the body uses to control itself.  Unlike enzymes, cytokines are involved in intracellular and intra-organ communication.  They are instrumental in maintaining homeostasis and are therefore an integral part of the body’s sleep regulation system.

Cytokines are involved in the regulation of sleep even when there is no disease in the body.  They interact with neurotransmitters and hormones and directly signal key neurons in the brain.

The interplay between the immune system and sleep is complex.  When we fall ill with a virus or bacterial infection we tend to need more sleep.  Since time immemorial people thought understood this was part of the body’s way of fighting the infection.  As we have learned more about the science, this ancient wisdom has proven true.

The  brain can figure out what the immune system is doing elsewhere in the body, and when infection is being battled, behavior changes, including sleep. Research indicates giving sleeping pills to patients in intensive care units may help them recover faster.

Given that cytokine concentrations and profiles change when we are sick, it is probable that cytokines are the involved in the change in sleep behavior when we are ill.

Even in normal sleep in healthy people, cytokines play a biotechpart in regulation. Interleukin-1 affects neuronal discharge in the hypothalamus where both melatonin and orexins are released.

If you read research in this field,  you see many references to the cytokines interleukin-1 beta and tumor necrosis factor (TNF).  Don’t be put off by the scary name of tumor necrosis factor.  It’s a widely distributed cytokine implicated in many physiological processes. Other cytokines, (e.g. IL-2, -15, -18, and Interferon) also affect the sleep cycle, especially during illness.

The 2003 National Sleep Disorders Research Plan says “There is some evidence that sleep loss and chronic sleep restriction may be associated, in addition to cytokines with other inflammatory markers (e.g., C-reactive protein) that could impact the development and severity of cardiovascular disease as well as daytime sleepiness and fatigue in sleep disorders.” Scientists have found that cytokines are part of the complex system of sleep regulation. In particular, they are part of the biochemical feedback loops involved in the homeostatic process.

The alterations in sleep architecture affect the course of infectious, endocrine, and inflammatory diseases.

Scientists have been able to artificially change sleep patterns in animals by injecting cytokines into their bloodstreams.  The symptoms of sleep loss can be produced by giving an animal extra IL1 or TNF. Both IL1 and TNF cause animals and humans to sleep more (specifically NREM sleep increases).  This is true whether the subject is ill or well.

In normal healthy sleep, brain temperature declines upon onset of N-REM sleep and rises when the brain goes into REM.  When the patient has a fever, sleep architecture changes.  N-REM sleep is fragmented, and REM sleep is suppressed.  Researchers have even been able to inject interleukin-1 into healthy rats and show that REM sleep can be brought to zero.  We shiver when we have a fever, but the body does not shiver during REM sleep.  Less REM sleep could be evolution’s way of accommodating fever as an immune system response to infection. Further, since the metabolic rate rises with body temperature and more energy is needed to just maintain body temperature, but sleeping, the body can avoid competing energy uses such as moving around.  This could be another evolutionary accommodation to fever using the sleep cycle.  The decline in REM and general fragmentation of sleep during a fever explains why people so often describe their nights as unsatisfying.

People with the psychiatric illness major depression tend to have both disturbed REM sleep and abnormal cytokine profiles.  These co-morbidities are not understood, but the co-incidence is further evidence of the complexity of both sleep regulation and the immune system.

Another interesting question is how hospitals essentially discourage sleep and how this can slow recovery times.  Hospitals tend to be noisy, the lighting is not very dark at night, and bed-bound patients do not get sufficient exposure to bright light during the day.  Maybe the hospitals of the future will be designed to help patients sleep.

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