Cedars-Sinai Research Institute University of California Los Angeles School of Medicine Los Angeles, California 90048
Address correspondence and requests for reprints to: Shlomo Melmed, M.D. Division of Endocrinology and Metabolism, Becker B-131, 8700 Beverly Boulevard, Los Angeles, California 90048.
![]() |
Introduction |
---|
![]() ![]() ![]() |
---|
Cytokines are small-to-medium size proteins that act as intercellular
regulators of cellular changes in metabolism and function. Most
cytokines have been well conserved throughout evolution, and many have
redundant biological activities, suggesting that cytokines comprise a
complex regulatory system for mediation of important physiological
processes. Cytokines mediate a wide range of pleiotropic biological
responses and regulate neuroendocrine function (1). For example, the
known functions of Interleukin (IL)-1 and tumor necrosis factor (TNF)
include local induction of adhesion molecules and chemotactic cytokines
as well as systemic actions such as fever, the acute phase response,
activation of bone marrow (2), and possibly, regulation of sleep. These
inflammatory cytokines have been demonstrated to have somnogenic
activity (3). TNF and IL-1ß enhance non-rapid-eye movement sleep,
increase the amplitude of electroencephalogram slow waves, and suppress
rapid-eye-movement sleep in animals (4).
In this issue of JCEM (see page 1313), Vgontzas and
colleagues provide a report that explores the role of circulating
TNF, IL-1ß, and IL-6 in disorders causing excessive daytime
sleepiness such as sleep apnea, narcolepsy, and idiopathic hypersomnia
(5). Their results reveal that plasma levels of TNF
were elevated in
patients with both sleep apnea and narcolepsy, IL-6 levels were
elevated only in sleep apnea patients, and interestingly, IL-1ß
levels were not altered in sleep disorders. The authors conclude that
TNF
and IL-6 may mediate sleepiness and fatigue in disorders
associated with excessive daytime sleepiness. Also, these authors
demonstrate for the first time an association between obesity and IL-6
levels. These results present the intriguing possibility of a novel
function for IL-6. Nonetheless, several issues warrant greater scrutiny
in the interpretation of these data.
The results of Vgontzas, et al. are based on cytokine levels
measured in single blood samples drawn at 06000700 on a single
morning following an 8 h polysomnographic-monitored sleep. There
is conflicting data in the literature regarding the timing of cytokine
release. Previous data have indicated that IL-1, IL-6, and TNF
increase during nocturnal sleep (6, 7, 8). Conversely, other reports have
shown that the production of TNF
and IL-1ß increases during
wakefulness (9). There are also reports purporting that cytokine
release follows circadian rhythmicity (7, 8). However, elevations of
these cytokines seen during wakefulness, shift with the period of sleep
deprivation (9), while circadian-dependent processes persist during
acute sleep deprivation (10). These findings suggest that circulating
cytokine levels may not be under circadian control. Given the
discrepancy regarding the relationship of peak cytokine levels to sleep
cycle or time of day, the significance of elevated early morning IL-6
and TNF
levels in patients with nocturnal sleep disturbance is less
clear.
The role of marked differences between the control subjects and sleep
apneic patients in age (24.1 yr ± 0.8 vs. 40.9 yr
± 2.2) and body mass index (BMI) (24.6 ± 0.7 vs.
40.5 ± 3.2) must be considered when drawing conclusions as to the
etiology of cytokine level differences between these groups. The
authors address this by assessing a stepwise multiple regression in
which BMI and age were found not to correlate with TNF values, but
BMI positively correlated with IL-6 values. These findings are
enigmatic given that elevated expression of TNF
messenger RNA, and
secretion of TNF
protein in adipose tissue has been demonstrated in
rodents (11) and humans (12). Failure to previously demonstrate
elevated plasma levels of TNF
in obese individuals was likely the
result of insufficient sensitivity of the assay. Indeed, TNF
plasma
levels were detectable in only 58% of obese animals (11). In the
present study by Vgontzas and colleagues (5), the lower limit of TNF
detection (0.18 pg/mL) appears to be nearly an order of magnitude lower
than previously reported assays. Thus, it is unclear if the elevated
levels of TNF
detected are related solely to obesity or to altered
sleep regulation associated with sleep apnea. Additional nonobese
control subjects with sleep apnea would be valuable in making this
distinction.
The suggestion that IL-6 plays a role in sleep regulation and the
demonstration of an association with obesity are novel. IL-6 was found
to be pyrogenic, but not somnogenic when injected
intracerebroventricularly in rabbits (13). Moreover, enhanced
expression of IL-6 messenger RNA was not detected in obese rodents
(11). TNF and IL-1 are known to induce IL-6 production (2). These
findings suggest that plasma IL-6 levels may be indirectly elevated
secondary to IL-1- or TNF
-mediated effects on sleep or obesity.
Further investigation is necessary to establish if IL-6 levels are
elevated independently of other cytokines and to determine the nature
of IL-6 involvement in sleep regulation.
The manuscript by Vgontzas and colleagues (5) is unique and pivotal in the field of neurocytokine regulation of sleep research because it represents one of the first reports in which cytokine levels are directly determined in the plasma of nonpharmacologically-stimulated individuals. A number of the technical obstacles faced by Vgontzas in conducting this study and interpreting the data are shared by all investigators in the field of neurocytokine regulation of sleep. Among these are insufficient sensitivity of assays in the past to detect normal physiological cytokine levels. For this reason, many of the published reports employed indirect assays involving stimulation of cytokine production with microbial products. It is unclear if exogenous stimulation provides proportional cytokine production, or even if such stimulation alters normal physiology. This technical shortcoming of the assays to accurately detect normal levels of cytokines has led to confusing and often contradictory reports in the literature. Indeed, circulating cytokine levels may not accurately reflect timing or levels of production in the central nervous system where presumably the regulation of sleep is occurring. Additional factors that may confound interpretation of plasma cytokine levels are bioavailability, presence of coregulators, variable time courses of degradation, or indirect activation of additional mediators. Finally, normal physiology is difficult to model in vitro, and experimentation with human subjects is, of necessity, limited in scope. Animal studies provide an in vivo model; however, the sleep-wake cycles of the commonly used laboratory animals do not approximate those of humans.
Despite these obstacles, the future of research into the physiologic regulation of sleep remains potentially productive. Cytokine regulation of physiological sleep is perhaps one of the most exciting areas of neuroendocrine investigation and promises to become even more so as the tools for inquiry become more readily available. Although the circadian rhythmic secretion of anterior pituitary hormones is well-documented, mechanisms mediating sleep-related hormone rhythms remain unclear. Sleep disorders are important causes of morbidity and mortality in endocrine and nonendocrine disease. Morbidity of hypothalamic disease, acromegaly, diabetes, and thyroid disorders may to a large extent be ascribed to dysregulated sleep function (14). Thus, studies such as that by Vgontzas and colleagues (5) will provide important information toward understanding the etiology of sleep disorders and perhaps aid in their prevention or cure. Furthermore, the versatile and redundant functions of various cytokines are just beginning to be elucidated. Knowledge of the functional interrelationships between these mediator proteins will lead to a greater understanding of one of the most fundamental biological processes.
Received February 18, 1997.
Accepted February 24, 1997.
![]() |
References |
---|
![]() ![]() ![]() |
---|