Department of Physiology and Biophysics
University of Tennessee
Memphis,Tennessee 38163
leep is regulated, in part, by humoral agents; e.g., many laboratories, beginning at the turn of the century, demonstrated that sleep-promoting substances accumulate in CSF during wakefulness which, when transferred to normal recipient animals, induce sleep. Within the past few years several sleep regulatory humoral agents have been identified; interletlkin-l (IL-1) and tumor necrosis factor a(TNFa) are perhaps the best characterized. Administration of IL-1 or TNF induces increased intensity of and duration of non-rapid eye movement sleep (NREMS), e.g., if mice are given 3 11glNFi.p. they get 81 min extra of NREMS during the first 9 h postinjection. In contrast, block IL-1 or TNF and spontaneous NREMS is inhibited; e.g., rabbits given a TNF soluble receptor lose about 25% of their NREMS for 6 h after injection. If IL-1 or TNF are blocked prior to sleep deprivation, or acute mild increases in ambient temperatures, or injection of microbial products the expected sleep responses fail to materialize. TNFa and IL-1b are normal brain products as are their receptors. Further, their rnRNA levels or protein levels vary with the sleep-wake cycle, e.g., rat hypothalamic TNF mRNA and TNF are highest just after light onset. Knockout strains of mice lacking either the IL-1 Type I receptor or the TNF 55-kD receptor sleep less than their strain controls, e.g., TNF 55-kD knockout mice sleep about 90 min less during daylight hours than the strain controls. Interestingly, the IL-1 receptor knockouts have less spontaneous sleep during night hours. Collectively, such data strongly implicate IL- 1 and TNF in physiological sleep regulation.
As cytokines, IL-1 and TNF are well characterized as immune response modifiers. Indeed, during infections profound changes in sleep occur that may be beneficial to the host. These infection-associated sleep responses are induced by specific microbial components; e. g., bacterial cell wall muramyl peptides and lipopolysaccharide or influenza viral double-strand RNA induce sleep responses. These microbial products also induce cytokine production and their somnogenic actions are attenuated if IL-1 or TNF are inhibited.
The humoral regulation of sleep involves complex cascades of biochemical events within the brain, perhaps analogous in part, to those events involved in immune cell regulation. Some of these regulatory events are known. For example, IL-1 induces TNF and growth hormone-releasing hormone (GHRH) production and anti-GHRH inhibits IL-1-induced sleep. Both IL-1 and TNF induce NO production. Inhibition of NO synthase inhibits spontaneous sleep and IL-1-induced sleep. Administration of exogenous NO-donors enhance sleep. Data such as these, coupled with the recent availability of knockout strains of mice lacking one or more of the genes included in the IL-1 and TNF families of molecules now allow a reductionalistic approach to the unraveling of the biochemical events and pathways involved in sleep regulation.
Suggested Review: Krueger, J. M. and J. A. Majde. Microbial products and cytokines in sleep and fever regulation. Crit. Rev. in Immunol. 14: 355-379, 1994.
