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The Interleukin 6 Signalling Pathway and the Effect of Sleep
Sleep, and the lack of sleep, can have a very large effect on the body and on how it functions. One of the functions that sleep has a large impact on is immunity (Dimitrov et al., 2006). Specifically, it has a large influence on the level of a cytokine known as interleukin-6, or IL-6 for short (Redwine, Hauger, Gillan and Irwin, 2000). IL-6 is given off by certain types of leukocytes, such as macrophages and T cells, and has a variety of functions including the promotion of inflammation during immune responses (Dimitrov et al., 2006). This essay will outline the biology of the IL-6 transduction pathway, what goes wrong in individuals who are sleep deprived, and also possible therapies that may be used in those sleep deprived individuals in order to prevent potential negative consequences.
In a healthy individual IL-6 mainly acts to promote inflammation as well as to aid in the production and maturation of B cells (Kishimoto, Akira, Narazaki and Taga, 1995). Although this is its main function, IL-6 also acts on T cells, macrophages, hepatocytes and hematopoietic progenitor cells in order to increase cellular proliferation (Kishimoto et al., 1995). It achieves these functions by initiating a signalling pathway which begins when IL-6 binds to the IL-6 receptor subunit of the IL-6 receptor complex found on the plasma membrane of cells. This complex also consists of the transmembrane protein called glycoprotein 130, or gp130, which plays a role in the induction of the signalling pathway. The signalling pathway can also be initiated by the binding of IL-6 to what is known as a soluble IL-6 receptor, or sIL-6R (Rose-John, Waetzig, Scheller, Grotzinger and Seegert, 2007). This complex can then travel to target cells and bind to the gp130 in the membrane of these cells, which is a process known as trans-signalling (Rose-John et al., 2007). Upon binding, gp130 creates either a gp130 homodimer or a gp130-LIFR heterodimer through ligand-induced dimerization (Kishimoto et al., 1995). This results in the activation of associated tyrosine kinases which are part of the Janus kinase, or JAK, family of kinases on the cytoplasmic side of the membrane (Kishimoto et al., 1995). These JAK kinases serve to initiate the intracellular transduction pathway which began in the extracellular environment by IL-6. JAK kinase achieves this by phosphorylating a transcription factor called signal transducer and activator of transcription 3, or STAT3 (Kishimoto et al., 1995). STAT3 then forms a homodimer and moves to the nucleus where it serves to initiate transcription of a number of genes (Hibi, Nakajima, and Hirano, 1996). One of these genes, called junB, eventually contributes to the growth and differentiation of B cells, which are essential to the healthy immune response linked to the IL-6 pathway (Nakajima and Wall, 1991).
In cases of sleep deprivation, this healthy immune response is weakened. In individuals who experience sleep deprivation, the amount of sIL-6R is reduced by approximately 70% (Dimitrov et al., 2006). In addition to this, IL-6 levels are also lower (Redwine et al., 2000). It has been shown that these diminished levels result because sleep has a restorative function and results in increased levels of the cytokine (Redwine et al., 2000). In this case, individuals who lack sleep undergo less formation of the IL-6/sIL-6R complex because the subunits are not as readily available and cannot join at the same rate. Due to the reduced formation of this complex, initiation of the transduction pathway also does not occur at the same rate. A combination of these factors means that the induction of the IL-6 pathway does not occur as effectively or as strongly when no sleep is occurring.
One major consequence of this failure to induce the IL-6 pathway is that the inflammatory response is weakened. Along with this consequence, the growth and differentiation of B cells does not occur at the same rate due to the fact that the signalling pathway which results in the transcription of genes responsible for proliferation and maturation of B cells is never initiated. Since B cells are the cells responsible for producing antibodies and aiding in the protection of the body from harmful antigens, as well as for maintaining T-cell memory, without an adequate amount the body is not as effective at mounting an immune response (Van Essen, Dullforce and Gray, 2000). As a result the individual becomes more susceptible to infection.
Aside from ensuring that an adequate amount of sleep is obtained, there are other possible future treatments for the effects that occur in association with reduced induction of the IL-6 pathway due to sleep deprivation. For example, this could possibly be done by developing a means to increase levels of both IL-6 and sIL-6R which would greatly reduce the effects associated with sleep deprivation. This could be done by injecting synthetic cytokines and proteins into the body. It may even be possible to inject a synthetic complex that could serve to induce the signalling pathway without the presence of naturally occurring IL-6 or sIL-6R. Through bypassing the portion of the pathway that involves naturally produced cytokines and receptors, it would be possible to rid the effects of these reduced levels and restore immune function.
Although IL-6 has many functions, it is especially crucial in the pro-inflammatory immune response. Factors such as a lack of sleep can be harmful to IL-6 signal transduction and can weaken the immune system. Aside from ensuring adequate rest, potential treatments for this problem may exist and could include the direct injection of a synthetic IL-6/sIL-6R complex. This would have the potential to decrease the effects linked to sleep deprivation and restore proper immune function.
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- Dimitrov, S., Lange, T., Benedict, C., Nowell, M.A., Jones, S.A., Scheller, J., Rose-John S., Born, J. (2006). Sleep enhances IL-6 trans-signaling in humans [electronic version]. The FASEB Journal, 20, 1599-1609.
- Hibi, M., Nakajima, K., & Hirano, T. (1996). IL-6 cytokine family and signal transduction: a model of the cytokine system [electronic version]. Journal of Molecular Medicine, 7, 1-12.
- Kishimoto, T., Akira, S., Narazakim, M., & Taga, T. (1995). Interleukin-6 family of cytokines and gp130 [electronic version]. Blood, 86 (4), 1243-1254.
- Nakajima, K., & Wall, R. (1991). Interleukin-6 signals activating junB and TIS11 gene transcription in a B-cell Hybridoma [electronic version]. Molecular and Cellular Biology, 11 (3), 1409-1418.
- Redwine, L., Hauger, R.L., Gillan, J.C., & Irwin, M. (2000). Effects of sleep and sleep deprivation on interleukin-6, growth hormone, cortisol, and melatonin levels in humans [electronic version]. The Journal of Clinical Endocrinology & Metabolism, 85 (10), 3597-3603.
- Rose-John, S., Waetzig, G.H., Scheller, J., Grotzinger, J., & Seegert, D. (2007). The IL-6/sIL-6R complex as a novel target for therapeutic approaches [electronic version]. Expert Opinion on Therapeutic Targerts, 11 (5), 613-624.
- Van Essen, D., Dullforce, P., & Gray, D. (2000). Role of B cells in maintaining helper T-cell memory [electronic version]. Phil. Trans. R. Soc. Lond. B, 355, 351-355.
This article looked into the various parts of the IL-6 pathway that were and were not affected by sleep. These parts included levels of IL-6, sIL-6R and the density of IL-6R on the membrane.
This article outlined the overlap in the IL-6 pathway as well as motifs in the mechanisms used. It also outlined the steps involved in the pathway.
This study looked at the overall interleukin-6 transduction pathway and the evidence in the literature that supports each step.
This article explained the pathway responsible for the activation of junB and TIS11. It also looked at the role that these genes play in the growth of B cells.
This paper talks about the increase in IL-6 levels during sleep. It also compares secretion levels to the amount and depth of sleep.
This article identifies trans-signalling as an alternative for initiating the IL-6 pathway. It also identifies sIL-6R as the receptor involved in trans-signalling and how the mechanism works to induce intra-cellular transduction.
The article looks into the role B cells plays in the body and in the creation and maintenance of T-cell memory in order to protect the body from future assault by harmful antigens.
I found this assignment to be very interesting. It helped me to understand a little bit more about the effects of sleep and sleep deprivation, aside from just exhaustion. It also emphasized the amount of damage that can be done by not obtaining adequate sleep. I had some difficulties in the search through the literature due to the fact that most articles only looked at one portion of the IL-6 pathway, or one effect of it. I also found that a number of different pathways were possible so it was difficult to focus on one specific pathway and result. However, I did manage to find a few very good review articles which helped to tie everything together and focus in on certain aspects. Overall, I found this problem summary to be quite enjoyable.