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Interleukin-6 levels fluctuate with the light–dark cycle in the brain and peripheral tissues in rats

https://doi.org/10.1016/j.bbi.2005.01.005Get rights and content

Abstract

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.

Introduction

Interleukin-6, an inflammatory cytokine, has received considerable attention for its potential roles in sleep regulation (Vgontzas et al., 1999, Vgontzas et al., 2004) and metabolism in adipose tissue (Wallenius et al., 2002). Sleep deprivation (SD) increases blood IL-6 in humans (Vgontzas et al., 1999, Vgontzas et al., 2004) and rodents (Hu et al., 2003). Although intracerebroventricular (icv) injection of human IL-6 does not affect sleep in rabbits (Opp et al., 1989), icv injection of rat IL-6 increases non-rapid eye movement sleep in rats (Hogan et al., 2003). In humans, subcutaneous injection of IL-6 increases slow wave sleep (SWS) with a considerable delay (Späth-Schwalbe et al., 1998). Adipose tissue is an important source of IL-6 in the blood (Mohamed-Ali et al., 1997). Increased serum IL-6 levels are associated with excessive daytime sleepiness (EDS) in obesity and apnea (Vgontzas et al., 1997, Vgontzas et al., 2000), as well as narcolepsy (Okun et al., 2004). IL-6 levels in the serum of humans (Redwine et al., 2000, Vgontzas et al., 1999, Vgontzas et al., 2004) and the pituitary gland of rats (Seres et al., 2004) are higher during the period dominated by sleep than the period dominated by wakefulness, whereas glucocorticoids display opposite secretion patterns. IL-6 and other inflammatory cytokines are potent stimulators of the hypothalamic–pituitary–adrenal (HPA) axis (Naitoh et al., 1988), which in turn inhibits these inflammatory cytokines to prevent the overshoot of their responses to immune challenges (Webster and Sternberg, 2004). We hypothesized that IL-6 levels in other tissues should also vary with the light-dark cycle as in the blood. To test our hypothesis, we determined IL-6 levels in the brain, blood, and adipose tissue in rats.

Section snippets

Methods

Male Sprague–Dawley rats (Charles River Laboratories, Wilmington, MA) between 80 and 90 days of ages were used in the experiment. All experimental protocols used in the experiment were approved by the Institutional Animal Care and Use Committee. Rats were kept at 23 °C room temperature on a 12:12 h light-dark cycle with light onset at 08:00. Rats were killed by decapitation every 4 h (10 rats/time point), starting at 09:00. The cortex, hippocampus, hypothalamus, and brainstem were dissected out on

Results

IL-6 levels in the brain, blood and adipose tissue are elevated during the light period compared to the dark period (Fig. 1). Cortex. There was a significant time effect [F (5,54) = 4.772, p < .002]. IL-6 levels were significantly higher at 09:00 compared to 21:00 and 01:00, and significantly higher at 17:00 compared to 01:00. Hippocampus. IL-6 levels varied significantly with time [F (5,54) = 7.809, p < .0001]. IL-6 levels were significant higher during the light period than the dark period except for

Discussion

Our study shows that IL-6 levels in the brain, blood and adipose tissue are elevated during the light period compared to the dark period. IL-6 levels are similarly varied in the rat pituitary gland (Seres et al., 2004). Our results are different from a human study, which did not find circadian variation of IL-6 (Born et al., 1997), and do not support the suggestion that the elevation of IL-6 during sleep was due to repeated blood drawing procedures (Haack et al., 2002) since our study was not

Acknowledgments

This research was supported by NIH Grants HL64415 to A.V. and HL64245 to J.F.

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