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About one third of a human life should be spent asleep (Zisapel, 2007). Unfortunately, 10 to 20% of Canadian adults sleep less than 6.5 hours per night (Statistics Canada, 2008). Lack of sleep has a negative effect on mood, cognitive function, and overall awareness (Zisapel, 2007). However, other than having a negative physiological effect, sleep deprivation can exert stress on many body systems (Zisapel, 2007). People with less than 7 hours of sleep have an increased mortality rate as found in a 22-year follow-up study by Hublin, et al. (2007). Sleep is an important regulatory mechanism and a lack of sleep has an effect on memory, insulin metabolism, weight gain, and immunity (Majde & Krueger, 2005). Changes in one of the important signalling molecules of the immune system, Interleukin-6 (IL-6), leads to severe complications such as autoimmune diseases (Naugler & Karin, 2007).
Interleukin-6 is an inflammatory cytokine produced mainly by monocytes and macrophages (Naugler & Karin, 2007). Its production is monitored by several transcription factors, such as Nuclear factor-kappa B (NF-ÎºB), AP-1, C/EPBÎ² (Naugler & Karin, 2007). Usually these transcription factors are stimulated by TNF-Î±, IL-1, and bacteria signalling molecules, which all are related to an inflammatory response (Naugler & Karin, 2007). IL-6 starts its signalling cascade by binding to its receptor, IL-6 RÎ±, on the surface of a cell (Naugler & Karin, 2007). This activates gp130, which activates the transcription factor STAT 3 (Naugler & Karin, 2007). Knockout mice lacking in the IL-6 gene have a weak immune response, including weak T-cell signalling and a lack of a quick acute phase response to an infection (Naugler & Karin, 2007). IL-6 is also a key effector in the differentiation of T-cells, specifically for the production of T helper 17 (Th17) cells (Naugler & Karin, 2007). These cells produce the signalling molecules Interleukin-17, an inflammatory cytokine (Paradowska, et al., 2007). In the immune response, IL-17 is responsible for the production of antimicrobial peptides (Naugler & Karin, 2007). As well, IL-17 can further activate other signalling cytokines (Naugler & Karin, 2007).
Sleep deprivation results in a significant increase of transcription factor, NF-ÎºB (Naidoo, 2009). When an individual is lacking sleep this increases stress on the endoplasmic reticulum system (Naidoo, 2009). There are three pathways that are activated to counteract the ER stress (Naidoo, 2009). When these three pathways are not successful in counteracting the negative effects of the lack of sleep, NF-ÎºB is activated (Naidoo, 2009). NF-Îºb stimulates transcription of the IL-6 gene, producing IL-6 (Atreya, et al., 2008). Increased IL-6 levels will stimulate many cell processes, among them, T-cell differentiation (Naugler & Karin, 2007).
Differentiation of T-lymphocytes into Th17 cells is mediated by IL-6 (Moisser et al., 2009). TGF-Î² begins the pathway, and IL-6 serves as a vital co-factor (Annunzianto, et al., 2009). There is still debate in the scientific community over the exact signalling in this pathway, however, it is agreed that IL-6 plays a very important role (Moisser et al., 2009).
As the level of Th17 cells increases, more IL-17 is produced (Paradowska, et al., 2007). Many studies have shown increased levels of IL-17, associated with autoimmune diseases such as rheumatoid arthritis (Paradowska, et al., 2007). Not only does IL-6 increase levels of IL-17 through differentiation of Th17 cells, but IL-17 can also have the signalling effect of increasing IL-6 (Paradowska, et al., 2007). In this way, this can become a cycle of degradation and increase the severity of autoimmune diseases like RA (Paradowska, et al., 2007). IL-17 has the ability to signal the degradation of cartilage by disassembly of collagen and proteoglycans (Paradowska, et al., 2007). Also, it blocks the formation of new collagen and proteoglycans (Paradowska, et al., 2007). The degradation of these two main components of articular cartilage is what causes RA (Moots, et al., 2009). The disruption and breakdown of this important connective tissue also affects the synovial membrane, which leads to painful swelling (Kotake, et al., 1999). As well, Il-17 can also promote the differentiation of osteoclasts (cells that promote bone resorption), which is also a part of the pathology of RA (Kotake, et al., 1999). Starting from sleep deprivation, IL-6 signalling increases, indirectly stimulating the production of Il-17 in the cells, which leads to autoimmune diseases such as RA.
Other than the obvious solution to sleep deprivation; sleeping more, there are few treatments available for the results of sleep deprivation (Vgontzas et al., 2007). One method of treating sleep deprivation could target expression of IL-6. If the transcription factor, NF-ÎºB, is inhibited in some way, then IL-6 would not be expressed and the signalling pathway would not continue (Atreya, et al., 2008). However, this inhibiting action would have to be very specific because IL-6 also has important positive functions, such an anti-inflammatory control (Zisapel, 2007).
Another treatment could involve inhibiting signalling of IL-6 to T-cells, so T-cells would not differentiate into Th17 cells, and IL-17 signalling would stop. For example, a drug used to treat RA is an IL-6 inhibitor, called Tocilizumab (Moots, et al., 2009). This monoclonal human antibody was shown to be effective in blocking the actions of IL-6 in mice and rat trials (Moots, et al., 2009). This type of treatment could be effective to combat the effects of sleep deficiency, not only for the effects on the immune system and autoimmune diseases, but also for other consequences of sleep deficiency (Zisapel, 2007). However, because of the wide variety of signaling effects of IL-6, especially in acute immune responses, excessive limiting the signaling of IL-6 may not be recommended (Majde & Krueger, 2005).
Sleep is a common trait for all mammals, yet humans underestimate its importance in maintaining many basic signaling pathways (Zisapel, 2007). Sleep has a serious effect on interleukin-6 levels and could potentially lead to autoimmune diseases such as rheumatoid arthritis (Naugler & Karin, 2007). By gaining a deeper understanding of these essential cell-signaling pathways, researchers can develop solutions for a healthier human population.