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