Effect of one night of sleep loss on changes in tumor necrosis factor alpha (TNF-α) levels in healthy men

Abstract

Total sleep deprivation in humans is associated with increased daytime sleepiness, decreased performance, elevations in inflammatory cytokines, and hormonal/metabolic disturbances.

To assess the effects of 40 h of total sleep deprivation (TSD) under constant and well controlled conditions, on plasma levels of TNF-α and its receptor (TNFR1), interleukin-6 (IL-6), cortisol and C-reactive protein (CRP), sleepiness and performance, 12 healthy men (29 ± 3 years) participated in a 5-days sleep deprivation experiment (two control nights followed by a night of sleep loss and one recovery night). Between 0800 and 2300 (i.e. between 25 and 40 h of sleep deprivation), a serial of blood sampling, multiple sleep latency, subjective levels of sleepiness and reaction time tests were completed before (day 2: D2) and after (day 4: D4) one night of sleep loss. We showed that an acute sleep deprivation (i.e. after 34 and 37 h of sleep deprivation) induced a significant increase in TNF-α (P < 0.01), but there were no significant changes in TNFR1, IL-6, cortisol and CRP. In conclusion, our study in which constant and controlled experimental conditions were realized with healthy subjects and in absence of psychological or physical stressors, an acute total sleep deprivation (from 34 h) was sufficient to induce secretion of pro-inflammatory cytokine such as TNF-α, a marker more described in chronic sleep restriction or deprivation and as mediators of excessive sleepiness in humans in pathological conditions.

Introduction

Mounting evidence from both observational and experimental research suggests that sleep disturbance and short sleep duration adversely impact human physical health [1] and mortality risk [2], [3]. The mechanisms by which altered sleep duration affects health are unclear, but experimental studies suggest altered sleep may impact levels of cytokines known to be important in regulating inflammation. Sleep deprivation has been found to alter immune responses [4] and to induce increases in circulating levels of inflammatory markers such as interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), and C-reactive protein (CRP) [5], [6]. Moreover, acute sleep loss, either total or partial, is associated with increased sleepiness and decrements in neurobehavioral performance [7], [8]. Also, more recently it has been shown that sleep loss is associated with next-day increase of proinflammatory cytokines, e.g. IL-6 and TNF-α [9], [10], [11], which have been proposed as mediators of pathological or experimentally induced sleepiness in humans and have been shown to be associated with an unfavorable metabolic profile, a higher risk of cardiovascular adverse events, and decreased longevity [9], [12]. However, the increases in IL-6 and TNF-α are very small, and contradictory results have also been reported. Frey et al. [13] looking at a single night of acute sleep loss under constant conditions of body posture, light levels, and nutritional intake, failed to see an increase, and in fact reported a decrease in IL-6 and CRP. In a study of mild sleep loss (2 h per night for seven nights in healthy men and women), men showed elevations of TNF-α as a consequence of sleep restriction, whereas women did not show this change [10]. In another study involving men who were sleep restricted to two 2 h naps per day for 4 days, Shearer et al. [5] found no increase in TNF-α or its receptors. In recent studies, Haack et al. [14] observed no significant changes in TNF-α or its soluble p55 receptor with men and women who underwent sleep reduction for 10 nights and Ruiz et al. [15] found no increase in TNF-α after two nights of total sleep deprivation (SD) or four nights of rapid eye movement (REM) SD. As yet, incompletely understood individual differences in vulnerability to sleep loss may underlie these discrepancies, or perhaps subtle but important differences in methods. Continuous use of an intravenous (IV) indwelling catheter across 24 h has been reported to be associated with an increase in IL-6 levels regardless of sleep or sleep deprivation [16]. The reported increase in IL-6 was hypothesized to be due to local inflammation at the IV site as higher IL-6 levels were reported for samples that were difficult to obtain, especially during sleep. The levels of other cytokines and soluble cytokine receptors, such as TNF-α and the soluble TNF receptors p55 and p75, are only slightly influenced by intravenous catheter [17].

In view of contradictory results related in different studies due to the experimental conditions, the aim of our study was to observe under constant and well controlled conditions the effect of an acute sleep deprivation in young healthy men (n = 12) on plasma levels of TNF-α and its receptor (tumor necrosis factor receptor-I: TNFR1), interleukin-6 (IL-6), cortisol and C-reactive protein (CRP), and to determine the daytime period in which the proinflammatory response is observed.