Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P05231 (interleukin-6)
 23,907 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Although the clinical effects of acute exposure to ultraviolet (UV) light--such as cutaneous inflammation, malaise, somnolence, chills and fever--have been appreciated many years, the underlying mechanisms mediating these effects are poorly understood. Interleukin-6 (IL-6) is a potent cytokine with a wide variety of biologic activities, including induction of fever and acute phase response. Because IL-6 is produced by keratinocytes in vivo and in vitro and because the release is enhanced by UV light, the present study was performed to investigate the effect of a single UV dose eliciting moderate to severe sunburn reaction on the production of IL-6 in vivo. Therefore, plasma of UV-treated human subjects was evaluated for IL-6 activity by testing its capacity to induce the proliferation of an IL-6-dependent hybridoma cell line (B9). In contrast to plasma samples obtained before UV exposure, post-UV-specimens contained significant levels of IL-6 peaking at 12 h after UV irradiation. Plasma IL-6 activity was neutralized by an antiserum directed against recombinant human IL-6, and upon HPLC gel filtration exhibited a molecular weight of around 20 kD. Moreover, plasma IL-6 levels correlated remarkably with fever course followed by an increase of acute phase proteins such as C-reactive protein. These data indicate that IL-6, which is released by keratinocytes following UV exposure, may gain access to the circulation and via its pyrogenic as well as acute phase-inducing effect may function as an important mediator of systemic sunburn reaction.
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PMID:Ultraviolet light induces increased circulating interleukin-6 in humans. 235 83

Sleepiness is a common complaint during infectious diseases, but the interaction between sleep and host defense mechanisms has been poorly explored in humans. We therefore studied the effect of endotoxin, a major pathophysiological factor in gram-negative bacterial infections, on sleep and on parameters of the primary host response in men. In a single-blind counterbalanced trial, 15 healthy volunteers received either placebo or Salmonella abortus equi endotoxin (0.4 ng/kg body wt) intravenously on two separate occasions. Nocturnal sleep was recorded, and rectal temperature and the plasma levels of tumor necrosis factor-alpha, interleukin-6, adrenocorticotropic hormone, and cortisol were monitored for 12 h. Endotoxin reduced the relative amounts of wakefulness (P < 0.05) and rapid-eye-movement (REM) sleep (P < 0.05) and increased the relative amount of non-REM sleep (P < 0.01). Electroencephalogram delta power during non-REM sleep, as measured by spectral analysis, was not altered by endotoxin. The endotoxin-induced changes in sleep structure were related temporally and quantitatively to the increases in rectal temperature and to the release of cytokines and neurohormones. It is concluded that cytokines and neurohormones mediate the effects of endotoxin upon sleep. The ensuing increase in non-REM sleep may be part of the adaptive host response to bacterial infections in humans.
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PMID:Influence of endotoxin on nocturnal sleep in humans. 839 56

Sleepiness is a common symptom of infectious diseases. However, the peculiarities and causes of impaired vigilance during host defense activation are largely unknown. It has been shown earlier that mild host defense activation by endotoxin does not affect daytime sleepiness and non-rapid eye movement (NREM) sleep in humans. In the present study we investigated the effects of a more intensive stimulation of the host defense by Salmonella abortus equi endotoxin (0.8 ng/kg), administered 12 h following host response priming by granulocyte colony-stimulating factor (300 micrograms s.c.), on daytime sleep and sleepiness in a placebo-controlled design in ten healthy men. Six equidistant polysomnographically monitored naps were scheduled across the day and the time course of subjective sleepiness was assessed. Endotoxin induced prominent increases in rectal temperature, and in the plasma levels of tumor necrosis factor-alpha, interleukin-6, interleukin-1 receptor antagonist, and cortisol. In the first nap, 1 h following endotoxin administration, total sleep time and NREM sleep stage 2 were reduced, whereas wakefulness and sleep onset latency were increased. Following this nap sleepiness transiently increased peaking prior to the second nap. However, this nap and the following ones were not influenced by endotoxin. These results suggest that prominent host defense activation reduces daytime NREM sleep and increases sleepiness. One cause of daytime sleepiness during infections may be prior sleep disruption and this kind of sleepiness may not necessarily be associated with an increased sleep pressure.
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PMID:Endotoxin-induced changes in sleep and sleepiness during the day. 980 18

Patients with pathologically increased daytime sleepiness and fatigue have elevated levels of circulating interleukin-6 (IL-6). The latter is an inflammatory cytokine, which causes sickness manifestations, including somnolence and fatigue, and activation of the hypothalamic-pituitary-adrenal axis. In this study, we examined: 1) the relation between serial measurements of plasma IL-6 and quantity and depth of sleep, evaluated by polysomnography; and 2) the effects of sleep deprivation on the nyctohemeral pattern of IL-6 secretion. Eight healthy young male volunteers were sampled for 24 h twice, at the baseline state, after a normal night's sleep and after total overnight sleep deprivation. At the baseline state, IL-6 was secreted in a biphasic circadian pattern with two nadirs at 0800 and 2100 and two zeniths at 1900 and 0500 (P < 0.01). The baseline amount of sleep correlated negatively with the overall daytime secretion of the cytokine (P < 0.05). Also, depth of sleep at baseline correlated negatively with the postdeprivation increase of daytime secretion of IL-6 (P < 0.05). Sleep deprivation changed the temporal pattern of circadian IL-6 secretion but not the overall amount. Indeed, during the post-deprivation period, the mean daytime (0800-2200 h) levels of IL-6 were significantly higher (P < 0.05), whereas the nighttime (2200-0600 h) levels were lower than the predeprivation values. Thus, sleep-deprived subjects had daytime oversecretion and nighttime under-secretion of IL-6; the former might be responsible for their daylong somnolence and fatigue, the latter for the better quality (depth) of their sleep. These data suggest that a good night's sleep is associated with decreased daytime secretion of IL-6 and a good sense of well-being and that good sleep is associated with decreased exposure of tissues to the proinflammatory and potentially detrimental actions of IL-6. Sleep deprivation increases daytime IL-6 and causes somnolence and fatigue during the next day, whereas postdeprivation decreases nighttime IL-6 and is associated with deeper sleep.
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PMID:Circadian interleukin-6 secretion and quantity and depth of sleep. 1044 46

Sleep apnea and associated daytime sleepiness and fatigue are common manifestations of mainly obese middle-aged men. The onset of sleep apnea peaks in middle age, and its morbid and mortal sequelae include complications from accidents and cardiovascular events. The pathophysiology of sleep apnea remains obscure. The purpose of this study was to test three separate, albeit closely related, hypotheses. 1) Does sleep apnea contribute to the previously reported changes of plasma cytokine (tumor necrosis factor-alpha and interleukin-6) and leptin levels independently of obesity? 2) Among obese patients, is it generalized or visceral obesity that predisposes to sleep apnea? 3) Is apnea a factor independent from obesity in the development of insulin resistance? Obese middle-aged men with sleep apnea were first compared with nonapneic age- and body mass index (BMI)-matched obese and age-matched lean men. All subjects were monitored in the sleep laboratory for 4 consecutive nights. We obtained simultaneous indexes of sleep, sleep stages, and sleep apnea, including apnea/hypopnea index and percent minimum oxygen saturation. The sleep apneic men had higher plasma concentrations of the adipose tissue-derived hormone, leptin, and of the inflammatory, fatigue-causing, and insulin resistance-producing cytokines tumor necrosis factor-alpha and interleukin-6 than nonapneic obese men, who had intermediate values, or lean men, who had the lowest values. Because these findings suggested that sleep apneics might have a higher degree of insulin resistance than the BMI-matched controls, we studied groups of sleep-apneic obese and age- and BMI-matched nonapneic controls in whom we obtained computed tomographic scan measures of total, sc, and visceral abdominal fat, and additional biochemical indexes of insulin resistance, including fasting plasma glucose and insulin. The sleep apnea patients had a significantly greater amount of visceral fat compared to obese controls (<0.05) and indexes of sleep disordered breathing were positively correlated with visceral fat, but not with BMI or total or sc fat. Furthermore, the biochemical data confirmed a higher degree of insulin resistance in the group of apneics than in BMI-matched nonapneic controls. We conclude that there is a strong independent association among sleep apnea, visceral obesity, insulin resistance and hypercytokinemia, which may contribute to the pathological manifestations and somatic sequelae of this condition.
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PMID:Sleep apnea and daytime sleepiness and fatigue: relation to visceral obesity, insulin resistance, and hypercytokinemia. 1072 86

Recent findings suggest that inflammatory cytokines are involved in sleep regulation. In part, this idea is based on studies showing that systemic levels of interleukin-6 (IL-6) are affected by sleep and sleep deprivation. However, intravenous (IV) catheters used for repetitive blood sampling were reported to increase local IL-6 production, which might confound sleep-dependent or circadian changes in the plasma concentrations of this cytokine. To further examine the effects of blood drawing procedures on IL-6 plasma levels, 12 healthy young male subjects participated in a 24-h cross-over study protocol involving sleep and sleep deprivation. Blood was collected half-hourly through an IV line and one additional sample was taken by a simple needle stick from the contralateral arm in parallel to the last sample from the catheter. Difficulties in blood sampling, the plasma levels of IL-6, cortisol and subjective sleepiness were quantified. In samples from the IV line there was a linear increase in IL-6 levels in both conditions, whereas the amount of IL-6 detected in the needle stick sample at the end did not differ from baseline. IL-6 levels were significantly higher in samples rated as difficult and those difficulties were more frequent during sleep compared to nocturnal wakefulness. IL-6 levels did not correlate to variations in sleepiness or cortisol levels. We conclude that variations in IL-6 plasma levels measured in samples from an IV catheter are caused, at least in part, by changes in local cytokine production rather than by physiological changes in circulating IL-6 levels.
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PMID:Diurnal variations of interleukin-6 plasma levels are confounded by blood drawing procedures. 1238 53

Thalidomide (Thal) can overcome drug resistance in multiple myeloma (MM) but is associated with somnolence, constipation, and neuropathy. In previous in vitro studies, we have shown that the potent immunomodulatory derivative of thalidomide (IMiD) CC-5013 induces apoptosis or growth arrest even in resistant MM cell lines and patient cells, decreases binding of MM cells to bone marrow stromal cells (BMSCs), inhibits the production in the BM milieu of cytokines (interleukin-6 [IL-6], vascular endothelial growth factor [VEGF], tumor necrosis factor-alpha [TNF-alpha]) mediating growth and survival of MM cells, blocks angiogenesis, and stimulates host anti-MM natural killer (NK) cell immunity. Moreover, CC-5013 also inhibits tumor growth, decreases angiogenesis, and prolongs host survival in a human plasmacytoma mouse model. In the present study, we carried out a phase 1 CC-5013 dose-escalation (5 mg/d, 10 mg/d, 25 mg/d, and 50 mg/d) study in 27 patients (median age 57 years; range, 40-71 years) with relapsed and refractory relapsed MM. They received a median of 3 prior regimens (range, 2-6 regimens), including autologous stem cell transplantation and Thal in 15 and 16 patients, respectively. In 24 evaluable patients, no dose-limiting toxicity (DLT) was observed in patients treated at any dose level within the first 28 days; however, grade 3 myelosuppression developed after day 28 in all 13 patients treated with 50 mg/d CC-5013. In 12 patients, dose reduction to 25 mg/d was well tolerated and therefore considered the maximal tolerated dose (MTD). Importantly, no significant somnolence, constipation, or neuropathy has been seen in any cohort. Best responses of at least 25% reduction in paraprotein occurred in 17 (71%) of 24 patients (90% confidence interval [CI], 52%-85%), including 11 (46%) patients who had received prior Thal. Stable disease (less than 25% reduction in paraprotein) was observed in an additional 2 (8%) patients. Therefore, 17 (71%) of 24 patients (90% CI, 52%-85%) demonstrated benefit from treatment. Our study therefore provides the basis for the evaluation of CC-5013, either alone or in combination, to treat patients with MM at earlier stages of disease.
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PMID:Immunomodulatory drug CC-5013 overcomes drug resistance and is well tolerated in patients with relapsed multiple myeloma. 1238

Obstructive sleep apnea (OSA) is a prevalent disorder particularly among middle-aged, obese men, although its existence in women as well as in lean individuals is increasingly recognized. Despite the early recognition of the strong association between OSA and obesity, and OSA and cardiovascular problems, sleep apnea has been treated as a 'local abnormality' of the respiratory track rather than as a 'systemic illness.' In 1997, we first reported that the pro-inflammatory cytokines interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNFalpha) were elevated in patients with disorders of excessive daytime sleepiness (EDS) and proposed that these cytokines were mediators of daytime sleepiness. Also, we reported a positive correlation between IL-6 or TNFalpha plasma levels and the body-mass-index (BMI). In subsequent studies, we showed that IL-6, TNFalpha, and insulin levels were elevated in sleep apnea independently of obesity and that visceral fat, was the primary parameter linked with sleep apnea. Furthermore, our findings that women with the polycystic ovary syndrome (PCOS) (a condition associated with hyperandrogenism and insulin resistance) were much more likely than controls to have sleep disordered breathing (SDB) and daytime sleepiness, suggests a pathogenetic role of insulin resistance in OSA. Other findings that support the view that sleep apnea and sleepiness in obese patients may be manifestations of the Metabolic Syndrome, include: obesity without sleep apnea is associated with daytime sleepiness; PCOS and diabetes type 2 are independently associated with EDS after controlling for SDB, obesity, and age; increased prevalence of sleep apnea in post-menopausal women, with hormonal replacement therapy associated with a significantly reduced risk for OSA; lack of effect of continuous positive airway pressure (CPAP) in obese patients with apnea on hypercytokinemia and insulin resistance indices; and that the prevalence of the metabolic syndrome in the US population from the Third National Health and Nutrition Examination Survey (1988-1994) parallels the prevalence of symptomatic sleep apnea in general random samples. Finally, the beneficial effect of a cytokine antagonist on EDS in obese, male apneics and that of exercise on SDB in a general random sample, supports the hypothesis that cytokines and insulin resistance are mediators of EDS and sleep apnea in humans. In conclusion, accumulating evidence provides support to our model of the bi-directional, feed forward, pernicious association between sleep apnea, sleepiness, inflammation, and insulin resistance, all promoting atherosclerosis and cardiovascular disease.
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PMID:Sleep apnea is a manifestation of the metabolic syndrome. 1589 51

Interleukin-6 (IL-6) is a pleiotropic cytokine produced by numerous types of immune and nonimmune cells and is involved in many pathophysiologic mechanisms in humans. Many studies suggest that IL-6 is a putative 'sleep factor' and its circadian secretion correlates with sleep/sleepiness. IL-6 is elevated in disorders of excessive daytime sleepiness such as narcolepsy and obstructive sleep apnea. It correlates positively with body mass index and may be a mediator of sleepiness in obesity. Also the secretion of this cytokine is stimulated by total acute or partial short-term sleep loss reflecting the increased sleepiness experienced by sleep-deprived individuals. Studies that evaluated the 24-hour secretory pattern of IL-6 in healthy young adults suggest that IL-6 is secreted in a biphasic circadian pattern with two nadirs at about 08.00 and 21.00, and two zeniths at about 19.00 and 05.00 h. In contrast, following sleep deprivation or in disorders of sleep disturbance, e.g., insomnia, IL-6 peaks during the day and, based on the level of stress system activity, i.e., cortisol secretion, contributes to either sleepiness and deep sleep (low cortisol) or feelings of tiredness and fatigue and poor sleep (high cortisol). In order to address concerns about the potential impact of differences of IL-6 levels between the beginning and the end of the 24-hour blood-drawing experiment, we proceeded with a cosinor analysis of 'detrended' data in young and old healthy individuals. This new analysis did not affect the biphasic circadian pattern of IL-6 secretion in young adults, while it augmented the flattened circadian pattern in old individuals in whom the difference was greater. Finally, IL-6 appears to be somnogenic in rats and exhibits a diurnal rhythm that follows the sleep/wake cycle in these animals. We conclude that IL-6 is a mediator of sleepiness and its circadian pattern reflects the homeostatic drive for sleep.
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PMID:IL-6 and its circadian secretion in humans. 1590 20

Interleukin-6 (IL-6) has been implicated in excessive daytime sleepiness (EDS) in humans, and exogenous IL-6 also induces sleep alterations both in humans and rats. The IL-6 levels in human blood vary with the light-dark cycle with IL-6 levels being high during the dark period and low during the light period, whereas in the pituitary of rats the IL-6 levels are elevated during the light period compared to the dark period. However, it is unknown whether IL-6 in the brain is affected by the light-dark cycle. We hypothesized that IL-6 levels in the brain are regulated by the light-dark cycles and are elevated during the period that is predominantly occupied by sleep. To test this hypothesis, we measured IL-6 levels in the brain, blood, and adipose tissue of rats across light-dark cycle every 4 h. IL-6 levels were significantly higher during the light period than during the dark period in the cortex, hippocampus and hypothalamus. In the brainstem, IL-6 levels did not significantly vary across the light-dark cycles. IL-6 levels in the blood and adipose tissues were also significantly higher during the light period than during the dark period. IL-6 levels were positively correlated between the blood and adipose tissue, between hypothalamus and blood, and between the hypothalamus and hippocampus. These observations suggest that IL-6 levels vary across the light-dark cycle among different tissues and that IL-6 levels are elevated both centrally and peripherally during the period predominantly occupied by sleep but decreased during the period that primarily consists of wakefulness.
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PMID:Interleukin-6 levels fluctuate with the light-dark cycle in the brain and peripheral tissues in rats. 1621 23


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