As a result of this downregulation, a subsequent decrease in cortisol, epinephrine and norepinephrine occurs, which contributes to the suppression of immune functions. On the other hand, levels of growth hormone, prolactin, melatonin and leptin increase. These molecules act as pro-inflammatory signals to activate the immune system, facilitating proliferation, differentiation and the generation of pro-inflammatory cytokines, including IL-1 and TNF-α4. At the onset of slow-wave sleep (SWS), pro-inflammatory cytokines and Th1 cytokines increase, but there remains uncertainty as to why this occurs. One theory is that during wakefulness, dangerous factors accumulate in the body, including reactive oxygen species (ROS), heat shock proteins (HSPs), and nucleotides. These molecules are thought to be similar to microbial molecules such as lipopolysaccharide (LPS) and other toll-like receptor ligands that enhance the production of pro-inflammatory cytokines via antigen-presenting cells (APC). Additionally, immune cells have their own internal clock that maintains periodic changes in pro-inflammatory cytokines4. In terms of specific cytokines, IL-1 and TNF-α have both been shown to increase NREM sleep in animal studies. It is therefore intuitive that due to inactivation or interference with the normal action of these two cytokines, spontaneous NREM sleep is diminished. For example, by preventing the activation of IL-1 through cleavage of its inactive form, NREM sleep is reduced3. It is also important to note that high levels of IL-1 inhibit sleep, which could be due to a feedback loop involving stimulation of corticosteroid-releasing hormone (CRH) by IL-1. In terms of immune regulation, IL-1 and TNF-α induce the activation of nuclear factor kappa B (NFκB), a transcription factor associated with substances that regulate