How Cytokines and Inflammation Relate to Sleep (Napping Encouraged!)

In this article we explore the science behind how cytokines and inflammation relate to sleep. So many individuals experience a lack of sleep in overall quantity or quality, whether it be due to nighttime awakenings to care for children or loved ones, a job that is demanding or requires work at evening hours, or other health conditions that contribute to insomnia. As healthcare practitioners, on a daily basis we likely see other aspects of health worsening when patients are unable to sleep. We often hear that sleep is healing and restorative, but what is the research that supports this?

Effects of Sleep Deprivation

One way we can learn about the benefits we derive from sleep is from sleep deprivation studies. Sleep deprivation has been shown to be associated with worse performance on cognitive tasks and motor performance,1,2 depression, feelings of burnout, decrease in feelings of empathy,3 increased vulnerability to infection,4 weight gain,5 and decreased insulin sensitivity.6 In fact, moderate sleep deprivation has been shown to impair motor and cognitive performance as much as the blood alcohol content of 0.1%, which in most locations exceeds the legal limit.7 These findings of course become issues of significant concern in job sectors where sleep deprivation is common such as medical residents or emergency room physicians and the military. Although we don’t all fit into these categories, that does not alleviate the importance that healthy sleep has for us all.

Cytokines and  Inflammation: The Effects of Diminished Sleep

Many cytokines, inflammatory markers, and hormones are impacted by sleep and the lack thereof. Many of these have a diurnal variation, and as such the impact of sleep is not surprising.8 The night-time decrease in cortisol and increase in melatonin is well known to be important for quality sleep, but cytokines such as interleukin (IL)-6 also normally increase at night and induce fatigue.9 Other markers of inflammation such as C-reactive protein (CRP), which does not have a diurnal variation in healthy subjects,10 have also been shown to be increased with both acute total and short-term partial sleep deprivation.11 Even more surprisingly, however, is that increases in CRP extend beyond the days with diminished sleep, as this parameter has been shown to continue to rise with two days of sleep recovery (8 hours/night) immediately after the sleep restriction.12 Other measured inflammatory cytokines, IL-1β, IL-6, and IL-17, also were increased with sleep restriction, with IL-17 continuing to remain elevated after two days of recovery sleep. In another study, prolonged acute sleep deprivation (34 hours) was shown to increase levels of the pro-inflammatory cytokine tumor necrosis factor alpha (TNF-α).13 The circadian rhythm of the secretion of IL-6 and TNF- α has been observed to be shifted in individuals with chronic insomnia,14 a factor which may be important to consider with interventions directed at inflammation in addition to other supportive therapies.

The Blood-Brain Barrier, Sleep, and Stress

If these factors alone are not alarming enough to cause us to retreat back to bed for an extra hour of sleep, this one may be. The integrity of the blood-brain barrier, which is crucial for protection of the central nervous system from circulatory proteins and toxins that may contribute to neuroinflammation and damage, also is affected by sleep restriction.15 Disruption of the tight junctions of the blood-brain barrier may be a factor that contributes to numerous neurodegenerative diseases including Alzheimer’s disease, amyotrophic lateral sclerosis, multiple sclerosis, and more.16 The low-grade inflammation associated with sleep loss and the previously mentioned increases in cytokines and inflammatory markers may be the factors leading to the altered function of the brain endothelial cells and tight junction proteins with decreased sleep.17 Stress also increases permeability of the blood-brain barrier via the release of corticotropin-releasing hormone (CRH).18 The stress-associated increase in blood-brain barrier permeability may be a factor that contributes to increased symptoms with stress in neuroinflammatory conditions such as multiple sclerosis. Elevations in CRH and cortisol, which it stimulates, are associated with disrupted sleep,19 signifying the importance of addressing the adrenal axis as well with neuroinflammation.

The Benefits of a Nap to Reduce Inflammation

Although the reports from patients and self-assessment on the benefits of napping may be quite varied, positive effects generally have been shown. A recent review surveying the impact of a scheduled nap in populations such as emergency medical services personnel and similar shift workers found that a nap had moderate yet significant positive effects on sleepiness both during and at the end of a shift.20 In placebo-controlled settings, a nap has been shown to have beneficial effects on sleep-deprivation symptoms as well as biochemical parameters after a night of total sleep loss. After taking a 2-hour nap, subjects experienced significantly less sleepiness, with trends towards improvements in psychomotor vigilance tasks.21 Biochemically, the 2-hour nap was found to reverse the changes caused by one night of sleep loss on cortisol and IL-6, with cortisol transiently decreasing during the nap and IL-6 remaining decreased for approximately 8 hours.

Regardless of status of health or disease, these changes, especially on a prolonged basis can have significant impact, shedding light on the importance of sleep for all.

Dr. Decker is a Naturopathic Doctor, graduating with honors from the National College of Natural Medicine (now the National University of Natural Medicine) in Portland, Oregon. Dr. Decker sees patients at her office in Portland, OR, as well as remotely, with a focus on gastrointestinal disease, mood imbalances, eating disorders, autoimmune disease, and chronic fatigue. Prior to becoming a naturopathic physician, Dr. Decker was an engineer, and obtained graduate degrees in biomedical and mechanical engineering from the University of Wisconsin-Madison and University of Illinois at Urbana-Champaign respectfully.  Dr. Decker continues to enjoy academic research and writing and uses these skills to support integrative medicine education as a writer and contributor to various resources. Dr. Decker supports Allergy Research Group® as a member of their education and product development team.
These statements have not been evaluated by the FDA. This product is not intended to diagnose, treat, cure, or prevent any disease.

 

References:
[1] Pilcher JJ, Walters AS. How sleep deprivation affects psychological variables related to college students’ cognitive performance. J Am Coll Health. 1997 Nov;46(3):121-6.
[2] Walker MP, et al. Practice with sleep makes perfect: sleep-dependent motor skill learning. Neuron. 2002 Jul 3;35(1):205-11.
[3] Rosen IM, et al. Evolution of sleep quantity, sleep deprivation, mood disturbances, empathy, and burnout among interns. Acad Med. 2006 Jan;81(1):82-5.
[4] Cohen S, et al. Sleep habits and susceptibility to the common cold. Arch Intern Med. 2009 Jan 12;169(1):62-7.
[5] Patel SR, et al. Association between reduced sleep and weight gain in women. Am J Epidemiol. 2006 Nov 15;164(10):947-54.
[6] Donga E, et al. A single night of partial sleep deprivation induces insulin resistance in multiple metabolic pathways in healthy subjects. J Clin Endocrinol Metab. 2010 Jun;95(6):2963-8.
[7] Williamson AM, Feyer AM. Moderate sleep deprivation produces impairments in cognitive and motor performance equivalent to legally prescribed levels of alcohol intoxication. Occup Environ Med. 2000 Oct;57(10):649-55.
[8] Kim TW, Jeong JH, Hong SC. The impact of sleep and circadian disturbance on hormones and metabolism. Int J Endocrinol. 2015;2015:591729.
[9] Vgontzas AN, et al. IL-6 and its circadian secretion in humans. Neuroimmunomodulation. 2005;12(3):131-40.
[10] Meier-Ewert HK, et al. Absence of diurnal variation of C-reactive protein concentrations in healthy human subjects. Clin Chem. 2001 Mar;47(3):426-30.
[11] Meier-Ewert HK, et al. Effect of sleep loss on C-reactive protein, an inflammatory marker of cardiovascular risk. J Am Coll Cardiol. 2004 Feb 18;43(4):678-83.
[12] van Leeuwen WM, et al. Sleep restriction increases the risk of developing cardiovascular diseases by augmenting proinflammatory responses through IL-17 and CRP. PLoS One. 2009;4(2):e4589.
[13] Chennaoui M, et al. Effect of one night of sleep loss on changes in tumor necrosis factor alpha (TNF-α) levels in healthy men. Cytokine. 2011 Nov;56(2):318-24.
[14] Vgontzas AN, et al. Chronic insomnia is associated with a shift of interleukin-6 and tumor necrosis factor secretion from nighttime to daytime. Metabolism. 2002 Jul;51(7):887-92.
[15] He J, et al. Sleep restriction impairs blood-brain barrier function. J Neurosci. 2014 Oct 29;34(44):14697-706.
[16] Zlokovic BV. The blood-brain barrier in health and chronic neurodegenerative disorders. Neuron. 2008 Jan 24;57(2):178-201.
[17] Hurtado-Alvarado G, et al. Blood-Brain Barrier Disruption Induced by Chronic Sleep Loss: Low-Grade Inflammation May Be the Link. J Immunol Res. 2016;2016:4576012.
[18] Esposito P, et al. Corticotropin-releasing hormone and brain mast cells regulate blood-brain-barrier permeability induced by acute stress. J Pharmacol Exp Ther. 2002 Dec;303(3):1061-6.
[19] Steiger A. Sleep and the hypothalamo-pituitary-adrenocortical system. Sleep Med Rev. 2002 Apr;6(2):125-38.
[20] Martin-Gill C, et al. Effects of Napping During Shift Work on Sleepiness and Performance in Emergency Medical Services Personnel and Similar Shift Workers: A Systematic Review and Meta-Analysis. Prehosp Emerg Care. 2018 Feb 15;22(sup1):47-57.
[21] Vgontzas AN, et al. Daytime napping after a night of sleep loss decreases sleepiness, improves performance, and causes beneficial changes in cortisol and interleukin-6 secretion. Am J Physiol Endocrinol Metab. 2007 Jan;292(1):E253-61.