The effects of 40 hours of total sleep deprivation on inflammatory markers in healthy young adults
Introduction
The acute phase response (APR) describes specific immune responses to tissue damage/infection and is aimed at promoting healing and recruitment of host defenses. The APR is also responsive to stress (e.g., psychosocial stress and exercise). One aspect of the APR includes stimulation of acute phase proteins (APPs), such as interleukin-6 (IL-6) released by immune cells and c-reactive protein (CRP) released by the liver (Black and Garbutt, 2002). APPs then stimulate the production of pro-inflammatory cytokines, cell adhesion molecules, and other inflammatory mediators that are important for tissue repair and host defense. While acute increases in these inflammatory markers are important for health, chronic elevations of inflammatory proteins have been implicated in the development and/or progression of health problems such as cardiovascular, endocrine, mood, and sleep disorders (Cesari et al., 2003, DeSouza et al., 1997, El-Solh et al., 2002, Maes et al., 1997, Okun et al., 2004, Ridker et al., 1997). A common problem associated with such disorders is disrupted sleep. Whether disturbed sleep contributes to the elevation of inflammatory proteins observed in these disorders has received little attention.
Sleep and sleep loss have been reported to be associated with alterations in immune cell production of inflammatory markers (Irwin, 2002). For example, Irwin et al. (2006) reported that a night of sleep restricted to 4 h increased pro-inflammatory cytokine gene expression. In addition, they reported that monocyte production of IL-6 and tumor necrosis factor-alpha (TNF-α) in response to lipopolysaccharide was greater following the night of sleep restriction. Dimitrov and colleagues reported that sleep increases levels of the soluble IL-6 receptor (Dimitrov et al., 2006) and that sleep is associated with alterations in balance between Th1 and Th2 cytokines (Dimitrov et al., 2004). Few studies have examined how sleep loss per se influences circulating inflammatory markers (Irwin, 2002). Circulating levels of IL-6 have been reported to be increased in healthy adults following 7 nights of 6-h vs. 8-h scheduled sleep (Vgontzas et al., 2004) and in African American male alcoholics during one night of 3.5-h vs. 7.5-h scheduled sleep (Irwin et al., 2004). Meier-Ewert et al. (2004) reported increased CRP levels following 10 nights of 4.2-h vs. 8.2-h scheduled sleep. Redwine et al. (2004) reported an increase in the cell adhesion molecule L-selectin during one night of 3.5-h vs. 7.5-h scheduled sleep. In several studies the effect of total sleep deprivation on IL-6 levels was examined and results from these studies are inconsistent. Specifically, Dinges et al., 1995, Born et al., 1997 reported that IL-6 levels did not change during 15–63 h of total sleep deprivation; whereas, Vgontzas et al. (1999b) reported increased IL-6 levels during 40 h of total sleep deprivation. Shearer et al. (2001) also reported that IL-6 levels were increased across 88 h of total sleep deprivation compared to partial sleep deprivation consisting of a 2-h nap opportunity every 12 h. However, Haack et al. (2002) reported that IL-6 levels were reduced during sleep deprivation compared to levels during sleep. Meier-Ewert et al. (2004) reported increased CRP levels during 64 h of total sleep deprivation; whereas, Dimitrov et al. (2006) reported that one night of sleep loss did not significantly alter CRP levels.
To our knowledge, no study to date has examined the effect of total sleep deprivation on cell adhesion molecules or anti-inflammatory cytokines. The aim of the current study, therefore, was to determine whether acute total sleep deprivation per se increases circulating levels of inflammatory markers in healthy young participants when sleep deprivation occurred under controlled laboratory constant routine conditions. We hypothesized that acute total sleep deprivation is a sufficient stimulus to trigger an increase in circulating inflammatory proteins (IL-6, CRP, interleukin-1β (IL-1β), ICAM-1, VCAM-1, and E-selectin). In addition, due to recent interest in the role of anti-inflammatory cytokines in cardiovascular health (Frostegard et al., 1999, Heeschen et al., 2003) and the balance between pro- and anti-inflammatory cytokines, we examined circulating levels of IL-1ra as a secondary analysis. We also examined salivary cortisol levels and subjective stress ratings during sleep deprivation.
Section snippets
Methods
Nineteen healthy individuals (9 females, 10 males) aged 28.05 ± 8.56 (mean ± SD) participated. Participants were free of any medical and psychiatric conditions determined by medical history, physical and psychological exams, blood and urine chemistries, electrocardiogram, and toxicology screens for drug use at screening and admission to the laboratory. In addition, participants had a normal body mass index (18.5–24.5 kg/m2), were non-smokers, and were free of medication use. Participants reported no
Results
Statistical results for plasma and saliva markers are presented for log transformed data; however, the raw data is presented in the figures to show the observed levels. Fig. 2a shows increases in sE-selectin during sleep deprivation compared to baseline (main effect of sleep deprivation F(1, 18) = 4.074, p = 0.059), and planned comparisons indicated significantly higher sE-selectin levels occurred in the afternoon and late evening. No significant main effects or interactions for sICAM-1 or sVCAM-1
Discussion
Our findings demonstrate that one night of total sleep deprivation in healthy young participants during strictly controlled constant routine conditions of bed rest, inactivity, dim light, and hourly nutrition intake, significantly altered circulating levels of pro- and anti-inflammatory cytokines and cell adhesion molecules. However, findings were mixed with some inflammatory markers significantly increasing and others significantly decreasing during sleep deprivation. Specifically, we found a
Acknowledgments
We thank the research participants. Supported by NIH R01-MH45130, NIH R01-HL073196, NIH MO1-RR02635, The Medical Foundation & Harold Whitworth Pierce Charitable Trust, Beverly Sears Graduate Student Grant—University of Colorado. D.F. supported by NIH F32 T32-AG15332, NIH NIA RO1-AG00279. We thank Adam T. Wertz and Jennifer L. Hageman for assistance with data analysis and Charles A. Czeisler for study support.
References (48)
The balance between IL-1 and IL-1Ra in disease
Cytokine Growth Factor Rev.
(2002)- et al.
Stress, inflammation and cardiovascular disease
J. Psychosom. Res.
(2002) - et al.
Inflammatory markers and cardiovascular disease (The Health, Aging and Body Composition [Health ABC] Study)
Am. J. Cardiol.
(2003) - et al.
Elevated levels of circulating cell adhesion molecules in uncomplicated essential hypertension
Am. J. Hyperten.
(1997) - et al.
Sleep associated regulation of T helper 1/T helper 2 cytokine balance in humans
Brain Behav. Immun.
(2004) - et al.
Sleep deprivation and human immune function
Adv. Neuroimmunol.
(1995) - et al.
Adhesion molecules in patients with coronary artery disease and moderate-to-severe obstructive sleep apnea
Chest
(2002) - et al.
Cytokine expression in advanced human atherosclerotic plaques: dominance of pro-inflammatory (Th1) and macrophage-stimulating cytokines
Atherosclerosis
(1999) - et al.
Diurnal variations of interleukin-6 plasma levels are confounded by blood drawing procedures
Psychoneuroendocrinology
(2002) - et al.
Sleep-deprived mice show altered cytokine production manifest by perturbations in serum IL-1ra, TNFa, and IL-6 levels
Brain Behav. Immun.
(2003)
Effects of sleep and sleep loss on immunity and cytokines
Brain Behav. Immun.
Nocturnal proinflammatory cytokine-associated sleep disturbances in abstinent African American alcoholics
Brain Behav. Immun.
Immune mediators in allergic rhinitis and sleep
Otolaryngol. Head Neck Surg.
Increased serum IL-6 and IL-1 receptor antagonist concentrations in major depression and treatment resistant depression
Cytokine
Effect of sleep loss on C-reactive protein, an inflammatory marker of cardiovascular risk
J. Am. Coll. Cardiol.
Exploring the cytokine and endocrine involvement in narcolepsy
Brain Behav. Immun.
The implication of obesity and central fat on markers of chronic inflammation: The ATTICA study
Atherosclerosis
Cellular adhesion molecule expression, nocturnal sleep, and partial night sleep deprivation
Brain Behav. Immun.
Soluble TNF-alpha receptor 1 and IL-6 plasma levels in humans subjected to the sleep deprivation model of spaceflight
J. Allergy Clin. Immunol.
Impact of sleep debt on metabolic and endocrine function
Lancet
Adrenocortical and gonadal-steroids during sleep-deprivation
Sleep
Interleukin-1beta modulates state-dependent discharge activity of preoptic area and basal forebrain neurons: role in sleep regulation
Eur. J. Neurosci.
Analytical performance of a highly sensitive C-reactive protein-based immunoassay and the effects of laboratory variables on levels of protein in blood
Clin. Diagn. Lab. Immunol.
Effects of sleep and circadian rhythm on human circulating immune cells
J. Immunol.
Cited by (248)
A randomized, placebo-controlled, double-blinded mechanistic clinical trial using endotoxin to evaluate the relationship between insomnia, inflammation, and affective disturbance on pain in older adults: A protocol for the sleep and Healthy Aging Research for pain (SHARE-P) study
2023, Brain, Behavior, and Immunity - HealthFrom symbiosis to dysbiosis in gut-consequence includes metabolic syndrome
2023, Microbial Biofilms: Challenges and Advances in Metabolomic StudySleep, Health, and Society
2022, Sleep Medicine ClinicsCircadian and homeostatic sleep-wake regulation of secretory immunoglobulin A (sIgA): Effects of environmental light and recovery sleep
2022, Brain, Behavior, and Immunity - HealthChallenges and Opportunities for Applying Wearable Technology to Sleep
2021, Sleep Medicine Clinics