Although sleep deprivation studies and insomnia studies both indicate that inflammatory cytokines are elevated subsequent to sleep loss, cytokines themselves appear to impact sleep. Animal studies indicate that administration of inflammatory cytokines have varying effects on sleep, depending on the nature, timing, and dose of cytokine administered. IL-6 has been described as a sleep modulator and its administration produces sleep fragmentation in rats (Hogan et al. 2003). IL-1 and TNF produce increases in nonrapid eye movement (NREM) sleep in mice, rats, and rabbits. However, the effects of proinflammatory cytokines on sleep continuity and fragmentation in humans is far less clear, partially because cytokine administration studies are rare. In healthy subjects, IL-6 and interferon-gamma (IFN- ) administration decreases amounts of SWS in the first half of the night and substantially increases SWS in the second half of the night (Spath-Schwalbe et al. 1998; Spath-Schwalbe et al. 2000). Along with these changes in sleep, administration of inflammatory cytokines produces feelings of fatigue and lethargy. In contrast, medications that block the effects of inflammatory cytokines appear to improve sleep and fatigue during the day. In rheumatoid arthritis (RA) patients with markedly poor sleep, a single dose administration of infliximab, a TNF antagonist approved for the treatment of RA, produced rapid, marked improvements in objective measurement of sleep efficiency and sleep latency, before any improvement in clinical markers such as joint pain and swelling (Zamarron, Maceiras, Mera, and Gomez-Reino 2004). The study was an open label trial with only six participants. Similarly, in a small sample of obese sleep apnea patients (n = 8), administration of etanercept, another TNF-antagonist medication, produced decreases in self-reported lethargy and less sleepiness, measured via increased sleep onset times in response to the multiple sleep latency test, a polysomnography-based measure of sleepiness (Vgontzas, Zoumakis, Lin, Bixler, Trakada, and Chrousos 2004b). These studies suggest that blockage of inflammatory cytokines lead to improved sleep.
Overall, translational research, using the framework and models generated by research from animal and human experimental studies, suggest that insomnia is associated with altered immune function, which includes increased inflammatory cytokine expression and decreased NK cell activity. These effects on immunity may be particularly important in clinical populations. NK cells play a role in tumor surveillance and decreased NK activity predicts poor prognosis in cancer patients. The prevalence of insomnia is as high as 50% in cancer patients (O'Donnell 2004), and fatigue and sleep complaints are increasingly being recognized as important detractors of quality of life in these patients (Carr et al. 2002). Given that clinical studies with insomnia patients and experimental studies on sleep loss both indicate decreases in NK activity, the effects of sleep impairment on immunity may have implications for the link between insomnia and cancer morbidity (Savard et al. 1999) and mortality (Kripke, Simons, Garfinkel, and Hammond 1979). The other primary immunologic finding in insomnia is inflammatory cytokine expression. In a 12-year follow-up of 1870 middle-aged men and women, sleep complaints (e.g., difficulty maintaining sleep) predicted coronary artery disease mortality (Mallon, Broman, and Hetta 2002). Much evidence documents that in cardiovascular disease, atherosclerotic plaque formation is driven by inflammatory processes (Ridker et al. 2000), and that increased levels of IL-6 are also implicated in the development of type 2 diabetes and hypertension (Boos and Lip 2006). Insomnia patients have elevated levels of the cytokines that promote low-grade inflammation and furthermore, sleep deprivation studies indicate that sleep loss produces increases in these cytokines as well. Together, these experimental and clinical studies are not only demonstrating links between sleep and immune processes, but are also identifying pathways through which chronic insomnia impacts health.
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