Department of Physiology and Biophysics, University of Tennessee, Memphis, Tennessee 38163

Several cytokines are somnogenic whether given systemically or centrally; the list includes interleukin-1 (IL-1) a and b, tumor necrosis factor (TNF) a and b, interferon-a (IFN-a), acidic fibroblast growth factor (FGF), insulin-like growth factor and prolactin. At least two cytokines inhibit sleep; IL-10 and the IL-1 receptor antagonist. Several cytokines appear to have little or no effect on sleep; IL-2, IL-6, IFNb and basic FGF. The major action of somnogenic cytokines is to increase the duration of slow-wave sleep (SWS). The intensity of SWS is also increased as evidenced by enhanced amplitudes of EEG slow-waves; similar supranormal slow-waves occur after sleep deprivation. Sleep responses to cytokines are dependent upon dose, time of day and species. For example, in rats low doses of IL-1 are somnogenic while high doses inhibit sleep. Intermediate doses are somnogenic at night but inhibit sleep during the day. Sleep and fever responses to cytokines can be separated, e.g., antipyretics block IL-1-induced fevers but not sleep responses and low doses of IL-1 elicit sleep but not fever responses in rats. Much evidence suggests that cytokines are involved in physiological sleep regulation. Thus, the ability of circulating leukocytes to produce IL-1 and TNF is dependent upon prior wakefulness. Plasma levels of TNF in humans vary directly with amplitudes of EEG slow-waves. Anti-IL-1 or anti-TNF antibodies inhibit sleep of normal animals. Similarly, soluble IL-1 receptors and soluble TNF receptors inhibit normal sleep. Further, these antibodies and soluble receptors block sleep rebound after sleep deprivation. CSF levels of IL-1 vary with the sleep-wake cycle. Finally, several cytokines (IL-1, TNF, FGF, prolactin) and their receptors are found in normal brain including areas known to be involved in sleep regulation. The mechanism by which cytokines enhance sleep remains largely unknown. They likely involve complex cascades of biochemical events within the brain perhaps analogous, in part, to those events involved in immune cell regulation. Nevertheless, some of the events involved in cytokine modified sleep are known. For example, growth hormone releasing hormone (GHRH) enhances sleep and anti-GHRH inhibits sleep. Anti-GHRH also inhibits IL-1-induced sleep. Further, both GHRH and IL-1 increase nitric oxide (NO) production. Inhibition of NO synthase inhibits spontaneous sleep and IL-1-induced sleep responses. Further, administration of exogenous NO-donors enhances sleep. Sleep inhibitory effects of high doses of cytokines could be mediated via corticotropin releasing hormone (CRF) or a-melanocyte stimulating hormone (a-MSH); both CRF and a-MSH inhibit normal sleep and IL-1-induced sleep. Collectively, this work provides strong evidence to support the conclusion that cytokines are part of physiological sleep mechanisms.