This present study was conducted to test the hypothesis that serum levels of sleep-related cytokines are involved in sleep disturbance in patients with RCT. To the best of our knowledge, this is the first study to investigate levels of sleep-related cytokines in patients with RCT. Our study demonstrated that serum concentration levels of TNF-α were significantly higher in the SD group compared with those of the NS and control groups. There were no associations between serum levels of sleep-related cytokines and clinical scores including VAS pain, UCLA, and PSQI scores. Our findings support a significant role of TNF-α in the pathophysiology of sleep disturbance as well as pain mechanism in patients with RCT, suggesting that TNF-α may be a therapeutic target for improving sleep disturbance in patients with RCT.
Numerous studies have demonstrated the association between poor sleep, inflammatory cytokines, and pain [11, 12, 15–17, 22]. Clinton et al.  reported that sleep deprivation and altered cytokine levels are associated with increased sensitivity to pain with sleepiness and rebound sleep. Heffner et al.  also reported that inflammatory and pain pathways can be the underlying mechanism responsible for the association between chronic pain and sleep disturbance. In patients with chronic pain such as fibromyalgia, chronic low back pain, osteoarthritis, or chronic fatigue syndrome, sleep disturbance was found to have significant associations with altered levels of cytokines . Previous studies have demonstrated that sleep disturbance in various diseases is associated with altered circulating levels of sleep-related cytokines including IL-1, IL-2, IL-6, IL-8, IL-10, and TNF-α [16–23]. These cytokines are also involved in inflammatory, anti-inflammatory, and pain pathways. Especially, IL-1α, IL-1β, IL-6, IL-8, and TNF-α have been found to play an important role in inflammation and pain due to RCT [3–8]. In comprehensive review of results from previous studies related sleep disturbance in various diseases, the present study included IL-1α, IL-1β, IL-2, IL-6, IL-8, IL-10, and TNF-α as sleep-related serum markers.
IL-1, IL-6, and TNF-α are pleiotropic, serving both physiologic and pathological functions including modulation of inflammation, sleep, and mood . Several studies reported that sleep deprivation is associated with increased levels of IL-6 and TNF-α [12, 20]. Additionally, poor sleep quality and increased frequency of sleep disturbance have been associated with elevated levels of IL-2 and IL-6 [12, 20]. Lee et al.  found that elevated levels of pro-inflammatory cytokines such as IL-6 and TNF-α were associated with poorer sleep quality in patients with schizophrenia. Cytokines including IL-1 and TNF-α partake in non-rapid eye movement sleep (NREMS) regulation under physiological and inflammatory conditions [11, 13].
Rockstrom et al.  found that TNF-α is involved in sleep regulation acting within an extensive tightly orchestrated biochemical network impacting sleep in health and disease. Clinton et al.  also described that cytokines such as IL-1 and TNF-α play in sleep regulation as they are currently the best-characterized sleep regulatory substances. Circulating levels of TNF-α are altered in many pathologies that exhibit sleep disturbances including chronic inflammation, rheumatoid arthritis, insomnia, and chronic fatigue syndrome . Rockstom et al.  reported that high circulating levels of TNF-α are associated with sleep problems and normalization of high TNF-α level improves sleep. Many symptoms induced by sleep loss, e.g. sleepiness, fatigue, poor cognition, enhanced pain sensitivity, can be elicited with an injection of exogenous IL-1 or TNF-α [11, 13, 14]. Clinically available inhibitors of IL-1 and TNF-α reduce the sleepiness and fatigue associated with rheumatoid arthritis and sleep apnea . The present study demonstrated that serum concentration levels of TNF-α were significantly higher in the SD group compared with those of the NS and control groups. Our findings support that TNF-α may play a significant role in pathophysiology of sleep disturbance as well as pain mechanism in patients with RCT and be a possible therapeutic target to improve sleep disturbance.
Heffner et al.  found that poorer sleep quality is associated with higher circulating levels of IL-6 in patients with chronic low back pain. Additionally, Ji et al.  found that IL-6 levels are positively correlated with cluster symptoms of pain, fatigue, depression, and sleep disturbance in patients with cancer. Wang et al.  found elevated IL-6 levels are associated with sleep disturbance in patients with major depressive disorder. However, the present study found that serum levels of IL-6 were significantly lower in the SD group compared with those of the NS and control groups. These are apparently contradictory results compared to those of previous studies. Pro-inflammatory and anti-inflammatory cytokines influence physiological sleep and sleep responses to pathological insult . IL-8 is a multifunctional chemokine that has a strong influence on the activation, regulation, and chemotactic effect of neutrophils and is significantly increased in patients with sleep disorders and various inflammatory conditions . IL-10, also known as human cytokine synthesis inhibitory factor, is an anti-inflammatory cytokine. Kim et al.  found that circulating IL-10 levels in those with idiopathic rapid eye movement sleep (REMS) disorder were significantly upregulated compared to those without idiopathic REMS disorder. Park et al.  found that increased IL-10 levels were related to low sleep quality in patients with temporomandibular disorder, supporting the finding that anti-inflammatory cytokines have a sleep-disrupting effect. Although the present study revealed serum levels of IL-8 and IL-10 were significantly higher in the SD group compared with those of the control group, differences were not significant when compared to the NS group. In light of these findings, further well-designed studies are needed to elucidate the connections between sleep disturbance and sleep-related cytokines such as IL-6, IL-8, and IL-10 in patients with RCT.
Recently, Ha et al.  reported melatonin may play a role as a mediator of night pain in patients with RCT or frozen shoulder. They found that melatonin increases the production of proinflammatory and pain-related cytokines such as IL-1α, IL-1β, IL-2, IL-6, and TNF-α . Circadian changes in melatonin levels may be an important contributor to the pathophysiology and treatment of patients with RCT. Further studies are needed to provide a better understanding of the role of melatonin and cytokines on symptoms including pain, inflammation, and sleep disturbance.
This study has several limitations. First, the control group was not matched for age and sex when compared to the SD group. However, the NS group was provided as an additional comparison group. Second, serum concentration levels of IL-1α, IL-1β, IL-2 were not measured as any value was out of the standard curve. Third, this is a cross-sectional study, and serial changes of sleep-related cytokines were not compared with symptoms after the operative procedure. Future prospective longitudinal studies with a wider spectrum of sleep-related mediators are needed to clarify these issues.