The effect of sleep deprivation

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The interleukin-6 (IL-6) signaling pathway is important for immune function and inflammation (Rose-John et al., 2006). IL-6 is a cytokine that promotes B cell differentiation, T cell growth and function, and production of both pro-inflammatory and anti-inflammatory mediators (Papanicolaou et al., 1998; Rose-John et al., 2006). Sleep deprivation is associated with increased daytime IL-6 production (Vgontzas et al., 1999). This may have negative systemic effects including exacerbation of inflammatory conditions (Vgontzas et al., 1999). There are at least two classes of IL-6 receptor inhibitors that show promise in decreasing IL-6 production (Rose-John et al., 2007; Mima and Nishimoto, 2009). These drugs may be used to both mitigate the effects of sleep deprivation and treat inflammatory conditions such as rheumatoid arthritis (Rose-John et al., 2007; Mima and Nishimoto, 2009).

There are two mechanisms of IL-6 signaling: classical signaling and trans-signaling (Rose-John et al., 2006). In classical signaling IL-6 binds to a membrane-bound receptor IL-6R, whereas in trans-signaling IL-6 binds to the soluble receptor sIL-6R (Rose-John et al., 2006). In both signaling mechanisms, the IL-6/(s)IL-6R complex associates with two membrane bound gp130 subunits (Rose-John et al., 2006). This association causes gp130 dimerization and initiation of a signal cascade (Rose-John et al., 2006). Classical IL-6 signaling only occurs in select cells because IL-6R is only present in the plasma membranes of hepatocytes, neutrophils, monocytes/macrophages, and lymphocytes (Rose-John et al., 2006). Since gp130 is expressed in most cell types, strong responses to trans-signaling are found in many target cells including neurons, smooth muscle cells, mesothelial cells, and endothelial cells (Rose-John et al., 2006).

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Gp130 dimerization activates multiple signal transduction pathways including the JAK/STAT3 pathway (Figure 1; Heinrich et al., 1998). Gp130 does not have a catalytic domain, so it relies on associated Janus kinase family proteins (JAKs) for tyrosine kinase activity (Hirano et al., 2000). Dimerization of gp130 results in JAK activation (Figure 1; Heinrich et al., 1998). Activated JAKs can then phosphorylate gp130 on six tyrosine residues, allowing for recruitment of more signal transducers to the gp130 cytoplasmic domain (Hirano et al., 2000). JAKs then phosphorylate bound signal transducers (Heinrich et al., 1998). These activated signal transducers leave gp130, dimerize, and enter the nucleus where they modulate gene expression (Figure 1; Heinrich et al., 1998).

IL-6 promotes cell growth, movement and differentiation (Hirano et al., 2000). Through the JAK/STAT3 pathway, IL-6 causes B cells to differentiate into antibody-forming plasma cells and causes monocytes to adopt a macrophage phenotype (Hirano et al., 2000; Rose-John et al., 2006). IL-6 signaling promotes B and T cell proliferation by increasing expression of anti-apoptotic genes (Hirano et al., 2000). Furthermore IL-6 affects leukocyte movement by modulating chemokine production in endothelial cells (Hirano et al., 2000). IL-6 mediated cell growth, movement, and differentiation is critical for the transition between acute innate responses and acquired immune responses (Rose-John et al., 2006). IL-6 assists in this transition by recruiting monocytes and lymphocytes to inflamed tissue while preventing neutrophil infiltration (Rose-John et al., 2006). The importance of IL-6 signaling is illustrated in the mouse model. When exposed to an infectious agent, IL-6 knockout mice have a much higher mortality rate than wildtype mice (Papanicolaou et al., 1998).

Although IL-6 has a critical role in normal immune function, IL-6 overexpression is detrimental (Papanicolaou et al., 1998). Plasma IL-6 levels are elevated in inflammatory disorders including rheumatoid arthritis and Crohn's disease (Papanicolaou et al., 1998; Rose-John et al., 2006). IL-6 contributes to disease progression by promoting retention of mononuclear cells within inflamed tissue (Rose-John et al., 2006). Both animal and clinical trials suggest that IL-6 inhibitors improve disease outcome for inflammatory conditions (Rose-John et al., 2007).

IL-6 has bimodal circadian secretion (Vgontzas et al., 1999). Sleep deprivation affects this expression pattern, causing increased daytime IL-6 expression and decreased nighttime IL-6 expression (Vgontzas et al., 1999). Increased daytime IL-6 expression has the potential to exacerbate inflammatory conditions and cause tissue damage (Vgontzas et al., 1999). Aside from its immune functions, IL-6 overexpression negatively affects bone health and the hypothalamic-pituitary-adrenal axis (beyond the scope of this paper, see Papanicolaou et al., 1998).

It may be possible to mitigate the effects of sleep deprivation on IL-6 expression using IL-6 inhibitors. Tocilizumab, a humanized IL-6R antibody, inhibits IL-6 binding to both IL-6R and sIL-6R (Mima and Nishimoto, 2009). This drug has completed phase III clinical trials for treating rheumatoid arthritis (Mima and Nishimoto, 2009). Tocilizumab may also be effective in treating sleep deprivation and other inflammatory conditions (Mima and Nishimoto, 2009). Another possible treatment involves the use of sgp130Fc, a competitive inhibitor of trans-signaling (Rose-John et al., 2007). In this treatment, IL-6/sIL-6R complexes bind to sgp130Fc instead of gp130, thus preventing sIL-6R from initiating a signal cascade (Rose-John et al., 2007). It is thought that since this treatment only partially inhibits IL-6 signaling, it may have fewer side effects than tocilizumab (Rose-John et al., 2007).

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Detrimental IL-6 overexpression is associated with inflammatory disorders and sleep deprivation (Rose-John et al., 2007; Vgontzas et al., 1999). These conditions can be treated with either toxilizumab or sgp130Fc (Mima and Nishimoto, 2009; Rose-John et al., 2007). It is important to limit the doses of these inhibitors because IL-6 is necessary for normal immune function and the transition from innate to acquired immunity (Rose-John et al., 2006, 2007). More research is needed to elucidate the factors that regulate circulating IL-6 levels.

References

  • Hirano, T., Ishihara, K., and Hibi, M. (2000). Roles of STAT3 in mediating cell growth, differentiation, and survival signals relayed through the IL-6 family of cytokine receptors. Oncogene, 19, 2548-2556.
  • This paper outlines the mechanism of STAT3 signaling and discusses the effect of this signaling pathway on the whole organism.

  • Heinrich, P. C., Behrmann, I., Muller-Newen, G., Schaper, F., and Graeve, L. (1998). Interleukin-6-type cytokine signaling through the gp130/Jak/STAT pathway. The Biochemical Journal, 334, 297-314.
  • This article offers a detailed mechanism of gp130/Jak/STAT signaling, giving structural information about the main proteins involved.

  • Mima, T. and Nishimoto, M. (2009) Clinical value of blocking IL-6 receptor. (2009). Current Opinion in Rheumatology, 21, 224-230.
  • This paper outlines some clinical success in using tocilizumab, a humanized IL-6R antibody to inhibit IL6 activity.

  • Papanicolaou, D. A., Wilder, R. L., Manolagas, S. C., and Chrousos, G. P. (1998) The pathophysiologic roles of interleukin-6 in human disease. Annals of Internal Medicine, 128, 127-137.
  • This review outlines the role of IL-6 in disease, discussing its effect on endocrine, metabolic, inflammatory, and autoimmune function.

  • Rose-John, S., Scheller, J., Elson, G., and Jones S. A. (2006). Interleukin-6 biology is coordinated by membrane-bound and soluble receptors: Role in inflammation and cancer. Journal of Leukocyte Biology, 80, 227-236.
  • This paper contrasts classical signaling with trans-signaling and discusses the role of trans-signaling in a variety of diseases.

  • Rose-John, S., Waetzig, G. H., Scheller, J., Grötzinger, J., and Seegert, D. (2007) The IL-6/sIL-6R complex as a novel target for therapeutic approaches. Expert Opinion on Therapeutic Targets, 11, 613-624.
  • This paper discusses the possibility of using recombinant sgp130 as a therapeutic sIL-6R inhibitor.

  • Vgontzas, A. N., Papanicolaou, D. A., Bixler, E. O., Lotsikas, A., Zachman, K., Kales, A., Prolo, P., Wong, M. L., Licinio, J., Gold, P. W., Hermida, R. C., Mastorakos, G., Chrousos, G. P. (1999). Circadian interleukin-6 secretion and quantity and depth of sleep. The Journal of Clinical Endocrinology and Metabolism, 84, 2603-2607.
  • This study determined that daytime IL-6 expression is elevated under conditions of sleep deprivation.

Personal reflection: It was fairly easy to find relevant papers regarding IL-6 signaling. Since IL-6 is involved in so many signaling pathways and has so many physiological effects, it was necessary to stay focused on a select few pathways and effects. It was harder to find information about the effect of sleep deprivation on levels of circulating IL-6. There was not a clear consensus in the literature regarding the effect of sleep deprivation on IL-6. I did not have space in this paper to discuss conflicting reports. I found the Vgontzas study most convincing.