Elsevier

Brain, Behavior, and Immunity

Volume 21, Issue 8, November 2007, Pages 1050-1057
Brain, Behavior, and Immunity

The effects of 40 hours of total sleep deprivation on inflammatory markers in healthy young adults

https://doi.org/10.1016/j.bbi.2007.04.003Get rights and content

Abstract

Inflammatory cytokines are released in response to stress, tissue damage, and infection. Acutely, this response is adaptive; however, chronic elevation of inflammatory proteins can contribute to health problems including cardiovascular, endocrine, mood, and sleep disorders. Few studies have examined how sleep deprivation acutely affects inflammatory markers, which was the aim of the current study. Nineteen healthy men and women aged 28.05 ± 8.56 (mean ± SD) were totally sleep deprived for 40 h under constant routine conditions. Pro-inflammatory markers: intracellular adhesion molecule-1 (ICAM-1), E-selectin, vascular adhesion molecule-1 (VCAM-1), c-reactive protein (CRP), interleukin-6 (IL-6), and interleukin-1β (IL-1β), and the anti-inflammatory cytokine interleukin-1 receptor antagonist (IL-1ra) were assayed in plasma. Daytime levels during baseline (hours 1–15 of scheduled wakefulness) were compared to daytime levels during sleep deprivation (hours 25–39 of scheduled wakefulness), thus controlling for circadian phase within an individual. Repeated measures ANOVA with planned comparisons showed that 40 h of total sleep deprivation induced a significant increase in E-selectin, ICAM-1, IL-1β, and IL-1ra, a significant decrease in CRP and IL-6, and no significant change in VCAM-1. Alterations in circulating levels of pro- and anti-inflammatory cytokines and cell adhesion molecules during sleep deprivation were consistent with both increased and decreased inflammation. These findings suggest that one night of sleep loss triggers a stress response that includes stimulation of both pro- and anti-inflammatory proteins in the healthy young subjects tested under our experimental conditions.

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.

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