Other Cytokines

Although there is good evidence to support a role for TNF and IL-1P in the impact of infections on sleep, the role of other cytokines is more ambiguous. This might reflect either the lack of a direct role or problems with experimental design. IL-2, IL-5, IL-18, INF-a, and INF-y usually increase the duration of sleep, whereas IL-4, IL-10, and IL-13 usually inhibit spontaneous sleep. The effect of IL-6 is less conclusive. In rats, it has been reported to be either somnogenic or to have no effect on sleep. By contrast, in humans, it decreases SWS in the first half of the night and increases SWS in the second half, with REM sleep decreased throughout. Shearer et al. (2001) studied soluble TNF-a receptor 1 (s'TNF-a R 1) and IL-6 plasma levels in humans subjected to the sleep deprivation model of spaceflight and observed that total sleep loss produced significant increases in plasma levels of s'TNF-a R 1 and IL-6, messengers that connect the nervous, endocrine, and immune systems. Carpagnano et al. reported higher concentrations of IL-6 in exhaled breath in OSAS patients than in healthy control subjects. These findings suggest that inflammation and oxidative stress are characteristic in the airways of OSAS patients and that their levels depend on the severity of the OSAS (Carpagnano, Karitov, Resta, Foschino-Barbaro, Gramiccioni, and Barnes 2002). The effects of all these cytokines might be due to their direct action on sleep or an indirect effect through other cytokines, in particular

TNF and/or IL-ip. Therefore, one possible explanation for the variation in sleep patterns that occur after different infections is that the various microorganisms elicit different host cytokine responses. Most proinflammatory cytokines seem to be somnogenic, whereas most anti-inflammatory cytokines are not. The inhibitory actions of the anti-inflammatory cytokines on sleep might be the result of their inhibition of brain proinflammatory cytokines (Bryant et al. 2004).

16.6.3 Proinflammatory Cytokines Circadian Rhythms in OSAS

It is an important aspect of sleep circadian rhythmicity, so diurnal variation in the immune response might support a link between sleep and immune system. Circulating lymphocytes and monocytes in the blood reach maximal values during the night (Born, Lange, Hansen, Molle, and Fehm 1997). Natural killer (NK) cells have very high level in the afternoon and decrease in number and activity just after midnight (Heiser 2000). There are many studies that investigated the variations in cytokine levels that occur during the sleep-wake cycle; but, it is difficult to measure them because endogenous cytokines levels are low. We studied circadian rhythms of IL-1, IL-6, and INF in children with severe OSAS, every second hour between 8.00 p.m. and 8.00 a.m., during a 12 channels polisomnography. The circadian rhythms of IL-1, IL-6, and INF were not significantly different from normal subjects (Nosetti et al. 2006). A preliminary study concludes that pediatric sleep-disordered breathing is associated with increasing circulating levels of TNF-a that closely correlate with the degree of sleep fragmentation.

Etzian et al. observed in adults with OSAS, plasma TNF levels peak during sleep, and circadian rhythm of TNF release disrupted by OSAS: The night peak of this cytokine had almost disappeared and an additional daytime peak had developed. Circadian variations in IL-1, IL-6, and INF did not differ from those in the controls. Because TNF-a is a known modulator of sleep, and CPAP therapy did not normalize TNF rhythms; TNF-a could play a pathophysiologic role in OSAS (Etzian, Linneman, Schlaak, and Zabel 1996).

Plasma IL-1P levels also have a diurnal variation, being highest at the onset of SWS (Gudewil 1992). The levels of other cytokines (including IL-2, IL-6, IL-10 and IL-12) and the production of T cells response to mitogens also change during the sleep-wake cycle (Redwine, Dang, Hall, and Irwin 2003). The production of macrophage-related cytokines (such as TNF) increases during sleep and this happens with the rise in monocyte numbers in the blood. The T-cell-related cytokines (like IL-2) increase during sleep, independent of migratory changes in T-cell distribution. All of these observed diurnal changes could be related to the effects of sleep or associated with the circadian oscillator. Sleep and the immune system therefore share regulatory molecules. These are interested in both physiological sleep and sleep in the acute-phase response to infection. This shows that sleep and the immune system are closely interconnected. It is likely that sleep settles the immune system through the action of centrally produced cytokines that are regulated during sleep. These endogenous cytokines are known to function through the autonomic nervous system and the neuroendocrine axis, however other studies could show that other system are used (Bryant et al. 2004).

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