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Partial sleep restriction activates immune response-related gene expression pathways: experimental and epidemiological studies in humans.

ABSTRACT: Epidemiological studies have shown that short or insufficient sleep is associated with increased risk for metabolic diseases and mortality. To elucidate mechanisms behind this connection, we aimed to identify genes and pathways affected by experimentally induced, partial sleep restriction and to verify their connection to insufficient sleep at population level. The experimental design simulated sleep restriction during a working week: sleep of healthy men (N = 9) was restricted to 4 h/night for five nights. The control subjects (N = 4) spent 8 h/night in bed. Leukocyte RNA expression was analyzed at baseline, after sleep restriction, and after recovery using whole genome microarrays complemented with pathway and transcription factor analysis. Expression levels of the ten most up-regulated and ten most down-regulated transcripts were correlated with subjective assessment of insufficient sleep in a population cohort (N = 472). Experimental sleep restriction altered the expression of 117 genes. Eight of the 25 most up-regulated transcripts were related to immune function. Accordingly, fifteen of the 25 most up-regulated Gene Ontology pathways were also related to immune function, including those for B cell activation, interleukin 8 production, and NF-?B signaling (P<0.005). Of the ten most up-regulated genes, expression of STX16 correlated negatively with self-reported insufficient sleep in a population sample, while three other genes showed tendency for positive correlation. Of the ten most down-regulated genes, TBX21 and LGR6 correlated negatively and TGFBR3 positively with insufficient sleep. Partial sleep restriction affects the regulation of signaling pathways related to the immune system. Some of these changes appear to be long-lasting and may at least partly explain how prolonged sleep restriction can contribute to inflammation-associated pathological states, such as cardiometabolic diseases.

SUBMITTER: Aho V

PROVIDER: S-EPMC3806729 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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Partial sleep restriction activates immune response-related gene expression pathways: experimental and epidemiological studies in humans.

Aho Vilma V Ollila Hanna M HM Rantanen Ville V Kronholm Erkki E Surakka Ida I van Leeuwen Wessel M A WM Lehto Maili M Matikainen Sampsa S Ripatti Samuli S Härmä Mikko M Sallinen Mikael M Salomaa Veikko V Jauhiainen Matti M Alenius Harri H Paunio Tiina T Porkka-Heiskanen Tarja T

PloS one 20131023 10

Epidemiological studies have shown that short or insufficient sleep is associated with increased risk for metabolic diseases and mortality. To elucidate mechanisms behind this connection, we aimed to identify genes and pathways affected by experimentally induced, partial sleep restriction and to verify their connection to insufficient sleep at population level. The experimental design simulated sleep restriction during a working week: sleep of healthy men (N = 9) was restricted to 4 h/night for ...[more]

PMID: 24194869

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Project description:Study objectivesThere is strong evidence that sleep disturbances are an independent risk factor for the development of chronic pain conditions. The mechanisms underlying this association, however, are still not well understood. We examined the effect of experimental sleep disturbances (ESDs) on three pathways involved in pain initiation/resolution: (1) the central pain-inhibitory pathway, (2) the cyclooxygenase (COX) pathway, and (3) the endocannabinoid (eCB) pathway.MethodsTwenty-four healthy participants (50% females) underwent two 19-day long in-laboratory protocols in randomized order: (1) an ESD protocol consisting of repeated nights of short and disrupted sleep with intermittent recovery sleep; and (2) a sleep control protocol consisting of nights with an 8-hour sleep opportunity. Pain inhibition (conditioned pain modulation, habituation to repeated pain), COX-2 expression at monocyte level (lipopolysaccharide [LPS]-stimulated and spontaneous), and eCBs (arachidonoylethanolamine, 2-arachidonoylglycerol, docosahexaenoylethanolamide [DHEA], eicosapentaenoylethanolamide, docosatetraenoylethanolamide) were measured every other day throughout the protocol.ResultsThe central pain-inhibitory pathway was compromised by sleep disturbances in females, but not in males (p < 0.05 condition × sex effect). The COX-2 pathway (LPS-stimulated) was activated by sleep disturbances (p < 0.05 condition effect), and this effect was exclusively driven by males (p < 0.05 condition × sex effect). With respect to the eCB pathway, DHEA was higher (p < 0.05 condition effect) in the sleep disturbance compared to the control condition, without sex-differential effects on any eCBs.ConclusionsThese findings suggest that central pain-inhibitory and COX mechanisms through which sleep disturbances may contribute to chronic pain risk are sex specific, implicating the need for sex-differential therapeutic targets to effectively reduce chronic pain associated with sleep disturbances in both sexes.Clinical trials registrationNCT02484742: Pain Sensitization and Habituation in a Model of Experimentally-induced Insomnia Symptoms. https://clinicaltrials.gov/ct2/show/NCT02484742.

Project description:Pain due to osteoarthritis (OA) is one of the most frequent causes of chronic pain. However, the mechanisms of OA pain are poorly understood. This review addresses the mechanisms which are thought to be involved in OA pain, derived from studies on pain mechanisms in humans and in experimental models of OA. Three areas will be considered, namely local processes in the joint associated with OA pain, neuronal mechanisms involved in OA pain, and general factors which influence OA pain. Except the cartilage all structures of the joints are innervated by nociceptors. Although the hallmark of OA is the degradation of the cartilage, OA joints show multiple structural alterations of cartilage, bone and synovial tissue. In particular synovitis and bone marrow lesions have been proposed to determine OA pain whereas the contribution of the other pathologies to pain generation has been studied less. Concerning the peripheral neuronal mechanisms of OA pain, peripheral nociceptive sensitization was shown, and neuropathic mechanisms may be involved at some stages. Structural changes of joint innervation such as local loss and/or sprouting of nerve fibers were shown. In addition, central sensitization, reduction of descending inhibition, descending excitation and cortical atrophies were observed in OA. The combination of different neuronal mechanisms may define the particular pain phenotype in an OA patient. Among mediators involved in OA pain, nerve growth factor (NGF) is in the focus because antibodies against NGF significantly reduce OA pain. Several studies show that neutralization of interleukin-1? and TNF may reduce OA pain. Many patients with OA exhibit comorbidities such as obesity, low grade systemic inflammation and diabetes mellitus. These comorbidities can significantly influence the course of OA, and pain research just began to study the significance of such factors in pain generation. In addition, psychologic and socioeconomic factors may aggravate OA pain, and in some cases genetic factors influencing OA pain were found. Considering the local factors in the joint, the neuronal processes and the comorbidities, a better definition of OA pain phenotypes may become possible. Studies are under way in order to improve OA and OA pain monitoring.

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Partial sleep restriction activates immune response-related gene expression pathways: experimental and epidemiological studies in humans.

Publications

Partial sleep restriction activates immune response-related gene expression pathways: experimental and epidemiological studies in humans.

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