The relationship of interleukin-1 and immune functions to sleep in humans.

Moldofsky, Harvey; Lue, Franklin A.; Eisen, Judith S; Keystone, Edward J.; Gorczynski, Reg

doi:10.1097/00006842-198605000-00001

Cited by 220 publications

(82 citation statements)

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“…29,36,[73][74][75] In healthy humans, the levels of IL-1b in blood plasma are highest at the onset of sleep. 16,76 This and other evidence, including circadian control of the production of somnogenic cytokines, indicates their involvement in physiological sleep regulation. Activated processing and release of cytokines by microglia (brain phagocytes) is caused in part by rising levels of extracellular ATP during wakefulness.…”

Section: Relationship Of Protein Fragments To Other Somnogensmentioning

confidence: 86%

“…56,65,66 As described below, these and other inflammatory cytokines can act as somnogens, indicating a major but incompletely understood connection between the immune system and sleep. 4,16,29,31,36,[67][68][69][70][71][72][73][74][75][76][77][78][79] Another potent endogenous somnogen is the PGD 2 prostaglandin, which preferentially induces NREM sleep. 11,28,80,81 The somnogenic activity of PGD 2 is mediated at least in part by the ability of brain-produced PGD 2 to increase the concentration of extracellular adenosine.…”

Section: Introductionmentioning

confidence: 99%

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Augmented generation of protein fragments during wakefulness as the molecular cause of sleep: a hypothesis

Varshavsky

2012

Protein Science

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Despite extensive understanding of sleep regulation, the molecular-level cause and function of sleep are unknown. I suggest that they originate in individual neurons and stem from increased production of protein fragments during wakefulness. These fragments are transient parts of protein complexes in which the fragments were generated. Neuronal Ca 21 fluxes are higher during wakefulness than during sleep. Subunits of transmembrane channels and other proteins are cleaved by Ca 21 -activated calpains and by other nonprocessive proteases, including caspases and secretases. In the proposed concept, termed the fragment generation (FG) hypothesis, sleep is a state during which the production of fragments is decreased (owing to lower Ca 21 transients) while fragment-destroying pathways are upregulated. These changes facilitate the elimination of fragments and the remodeling of protein complexes in which the fragments resided. The FG hypothesis posits that a proteolytic cleavage, which produces two fragments, can have both deleterious effects and fitness-increasing functions. This (previously not considered) dichotomy can explain both the conservation of cleavage sites in proteins and the evolutionary persistence of sleep, because sleep would counteract deleterious aspects of protein fragments. The FG hypothesis leads to new explanations of sleep phenomena, including a longer sleep after sleep deprivation. Studies in the 1970s showed that ethanol-induced sleep in mice can be strikingly prolonged by intracerebroventricular injections of either Ca 21 alone or Ca 21 and its ionophore (Erickson et al., Science 1978;199:1219-1221 Harris, Pharmacol Biochem Behav 1979;10:527-534; Erickson et al., Pharmacol Biochem Behav 1980;12:651-656). These results, which were never interpreted in connection to protein fragments or the function of sleep, may be accounted for by the FG hypothesis about molecular causation of sleep.

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Section: Relationship Of Protein Fragments To Other Somnogensmentioning

confidence: 86%

Section: Introductionmentioning

confidence: 99%

Augmented generation of protein fragments during wakefulness as the molecular cause of sleep: a hypothesis

Varshavsky

2012

Protein Science

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“…With respect to IL-1, there are diurnal rhythms to IL-1 message and protein that are in phase with major sleep periods (Moldofsky et al, 1986;Lue et al, 1987;Taishi et al, 1998). Administration of IL-1 into laboratory animals increases the amount of time spent in NREM sleep, whereas antagonizing the IL-1 system with receptor antagonists, soluble receptors or antibodies reduces NREM sleep [reviewed (Krueger et al, 2001; Opp and Toth, 2003;Opp, 2005)].…”

Section: Introductionmentioning

confidence: 99%

Effects of i.c.v. administration of interleukin-1 on sleep and body temperature of interleukin-6-deficient mice

Olivadoti

Opp

2008

Neuroscience

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Cytokines in brain contribute to the regulation of physiological processes and complex behavior, including sleep. The cytokines that have been most extensively studied with respect to sleep are interleukin (IL)-1β, tumor necrosis factor (TNF)-α, and IL-6. Administration of these cytokines into laboratory animals, or in some cases into healthy human volunteers, increases the amount of time spent in non-rapid eye movement (NREM) sleep. Although antagonizing the IL-1 or TNF systems reduces the amount of time laboratory animals spend in NREM sleep, interactions among these three cytokine systems as they pertain to the regulation of physiological NREM sleep are not well understand. To further elucidate mechanisms in brain by which IL-1β, TNFα, and/or IL-6 contribute to NREM sleep regulation, we injected recombinant murine IL-1β (muIL-1β) into C57BL/6J mice and into IL-6-deficient mice (IL-6 knockout, KO). IL-6 KO (B6.129S6-Il6 tm1Kopf ; n = 13) and C57BL/6J mice (n = 14) were implanted with telemeters to record the electroencephalogram (EEG) and core body temperature, as well as with indwelling guide cannulae targeted to one of the lateral ventricles. After recovery and habituation, mice were injected intracerebroventricularly (ICV) just prior to dark onset on different days with either 0.5 µl vehicle (pyrogen-free saline; PFS) or with 0.5 µl PFS containing one of four doses of muIL-1β (2.5 ng, 5 ng, 10 ng, 50 ng). No mouse received more than two doses of muIL-1β, and administration of muIL-1β doses was counter-balanced to eliminate potential order effects. Sleep-wake behavior was determined for 24 h after injections. ICV administration of muIL-1β increased in NREM sleep of both mouse strains in a dose-related fashion, but the maximal increase was of greater magnitude in C57Bl/6J mice. muIL-1β induced fever in C57Bl/6J mice but not in IL-6 KO mice. Collectively, these data demonstrate IL-6 is necessary for IL-1 to induce fever, but IL-6 is not necessary for IL-1 to alter NREM sleep.

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“…It is well known that NK cells defend against tumor cell growth and viral infections in human cellular immune systems, and that NK cell functions are variously influenced by workload [15][16][17] , mental health 20-22, 24, 25) , and life style [34][35][36][37][38][39][40][41][42][43][44][45][46][47][48][49][50] . As for life style, it was reported that reduction of NK cell functions was associated with cigarette smoking [34][35][36][37][38] , shortened daily sleep 17) , disturbed sleep [39][40][41] , circadian rhythm (high activity in the morning and low activity at night) [42][43][44][45] , and excessive physical exercise 46,47) .…”

Section: Discussionmentioning

confidence: 99%

An Occupational Health Study of Emergency Physicians in Japan: Health Assessment by Immune Variables (CD4, CD8, CD56, and NK Cell Activity) at the Beginning of Work

Okamoto¹,

Tsunoda²,

Teruya

et al. 2008

Journal of Occupational Health

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An Occupational Health Study of E m e r g e n c y P h y s i c i a n s i n J a p a n : H e a l t h Assessment by Immune Variables (CD4, CD8, CD56, and NK cell activity) at the Beginning of Work: Hiroteru OKAMOTO, et al. Department of Preventive Medicine and Public Health, School of Medicine, Kyorin University-This study was conducted to evaluate the occupational health of Japanese physicians in emergency medicine. Subjects participating in this study were eighty-nine physicians working at 12 medical facilities (10 critical care emergency centers) in Japan. Participants were asked to complete a questionnaire of work conditions and to provide blood samples for immune variable measurements (CD4, CD8, CD56 and natural killer cell (NK cell) activity) before commencing their work. The data collected from seventy-four of 89 participating physicians were analyzed. The traditional work group comprised of 39 emergency physicians, who were significantly overworked compared to other two groups: the shift work group and the day work group. Among these three groups, no immune variable was significantly different except lymphocyte, number of CD4, and NK cell activity; and the NK cell activity of the shift work group was significantly lower than those of the traditional work group (p<0.01) and the day work group (p<0.01) in terms of Bonferroni's multiple comparison, probably due to circadian rhythm. It was indicated that NK cell activity was significantly lower in samples collected at night versus in the morning (OR=8.34, 95%CI: 1.95-35.6, p<0.01) through multiple logistic regression analyses. NK cell activity was significantly lower in individuals taking 0-3 days off per month, as compared to those taking 4 or more days off (OR=4.65, 95%CI: 1.27-17.0, p=0.02), according to multiple logistic regression analyses. Therefore, the low NK cell activity appears to have reflected the extent of fatigue arising from physicians' overwork. Overwork would have been a potential risk for the physicians' health, resulting in a lower quality of Japanese emergency medical services than that which could have been achieved otherwise. This study suggests that it would be better for the Japanese emergency physicians to take 4 or more days off per month for their health and the quality of their services. (J Occup Health 2008; 50: 136-146)

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The relationship of interleukin-1 and immune functions to sleep in humans.

Cited by 220 publications

References 0 publications

Augmented generation of protein fragments during wakefulness as the molecular cause of sleep: a hypothesis

Augmented generation of protein fragments during wakefulness as the molecular cause of sleep: a hypothesis

Effects of i.c.v. administration of interleukin-1 on sleep and body temperature of interleukin-6-deficient mice

An Occupational Health Study of Emergency Physicians in Japan: Health Assessment by Immune Variables (CD4, CD8, CD56, and NK Cell Activity) at the Beginning of Work

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