Humoral links between sleep and the immune system: research issues

In the last twenty years we have realized that the immune system synthesizes a class of peptides, termed cytokines, that play a central role in alerting the brain to ongoing inflammation in peripheral tissues. Among the brain's responses to proinflammatory cytokines, or agents that induce these cytokines, are certain alterations in sleep profiles. Characteristically there is an increase in non-rapid eye movement sleep (NREMS), and NREMS intensity is often accompanied by a decrease in rapid eye movement sleep (REMS). Cytokines appear to play a role in normal sleep regulation; during pathology, higher levels of cytokines amplify the physiological cytokine sleep mechanisms. In this review we summarize the extensive literature on the roles of interleukin-1 (IL-1) and tumor necrosis factor-alpha (TNF-alpha) in sleep regulation, and their interactions with the neuropeptides growth hormone-releasing hormone (GHRH) and corticotropin-releasing hormone (CRH). We reach the tentative conclusion that the sleep-promoting actions of IL-1 and GHRH are mediated via anterior hypothalamic neurons that are receptive to these substances. It also seems likely that TNF-alpha and CRH also influence these neurons. In addition, we discuss an array of research issues raised by these studies that remain to be resolved.