IL-6 Trans-Signaling via the Soluble IL-6 Receptor: Importance for the Pro-Inflammatory Activities of IL-6

Institute of Biochemistry, Christian-Albrechts-University of Kiel, Kiel, Germany.
International journal of biological sciences (Impact Factor: 4.51). 10/2012; 8(9):1237-47. DOI: 10.7150/ijbs.4989
Source: PubMed


Interleukin-6 (IL-6) is a cytokine with many activities. It has functions in the regulation of the immune system and the nervous system. Furthermore, IL-6 is involved in liver regeneration and in the metabolic control of the body. On target cells, IL-6 binds to an 80 kDa IL-6 receptor (IL-6R). The complex of IL-6 and IL-6R associates with a second protein, gp130, which thereupon dimerizes and initiates intracellular signaling. Whereas gp130 is expressed on all cells, IL-6R is only present on few cells in the body including hepatocytes and some leukocytes. Cells, which do not express IL-6R cannot respond to the cytokine, since gp130 alone has no measurable affinity for IL-6. Interestingly, a soluble form of IL-6R (sIL-6R) comprising the extracellular portion of the receptor can bind IL-6 with a similar affinity as the membrane bound IL-6R. The complex of IL-6 and sIL-6R can bind to gp130 on cells, which do not express the IL-6R, and which are unresponsive to IL-6. This process has been called trans-signaling. Here I will review published evidence that IL-6 trans-signaling is pro-inflammatory whereas classic IL-6 signaling via the membrane bound IL-6R is needed for regenerative or anti-inflammatory activities of the cytokine. Furthermore, the detailed knowledge of IL-6 biology has important consequences for therapeutic strategies aimed at the blockade of the cytokine IL-6.

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Available from: Stefan Rose-John
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    • "sgp130 can bind to the IL-6/sIL-6R complex and inhibit binding of the complex to the membrane-bound gp130 (mgp130). In physiological conditions, the concentration of sgp130 is around 400 ng ml −1 (Rose-John, 2012) and thus higher than the concentration of the IL-6/sIL-6R complex and also has a higher affinity for the IL-6/sIL-6R complex than the affinity of IL-6 for the sIL-6R. Similarly to IL-6, there is also a soluble version of the CNTF receptor, called sCNTFR (Mihara et al., 2012). "

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    • "Bearing this in mind, a likely explanation for this result is that the suppression of the first line of defences by androgens could increase susceptibility to pathogens or parasites, leading to a subsequent activation of these immunological variables . Il-6 is a protein required for the activation of the immune system (Rose-John, 2012) and is considered a main inflammatory marker (Kishimoto, 2005; Raman et al., 2013). It is assumed that mounting an immune response has energetic and/or nutrient costs which may interfere with metabolic processes (Demas et al., 1997), resulting in a possible loss of body weight. "
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    • "However, during inflammatory conditions, IL-6 levels can increase up to a millionfold [10], whereas serum concentrations of sIL-6R and sgp130 show much smaller differences between healthy and diseased and in most cases do not rise by more than a factor of 2 [15]. These concentrations imply that IL-6, once secreted, will bind to sIL-6R in the serum and this complex will associate with sgp130, and thereby be neutralized [8]. Only when IL-6 levels exceed the levels of sIL-6R and sgp130, IL-6 can act systematically-as seen under septic conditions [10]. "
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