IL-6 Trans-Signaling via the Soluble IL-6 Receptor: Importance for the Pro-Inflammatory Activities of IL-6
By S. Rose‐John. International Journal on Biological Sciences, 2012
1,022 citations recorded by the source corpus.
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.
Subfields: Immunology, Oncology
View Paper: https://www.semanticscholar.org/paper/0c0245f5190cc27e1da82f2770feb9ff678e86c2
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Citations in the corpus
- Cytokine release syndrome (2018, background): “This soluble IL-6/IL-6 receptor complex binds to gp130 and therefore can also induce signaling in cell types that do not express membrane bound IL-6 receptors [59].”
- Identification of Predictive Biomarkers for Cytokine Release Syndrome after Chimeric Antigen Receptor T cell Therapy for Acute Lymphoblastic Leukemia (2016, background): “In other IL6-mediated diseases, IL6 levels often go up and sIL6R levels either increase or decrease after treatment as the interaction between IL6R and IL6 is blocked (21, 23, 24).”
- IL-6R/STAT3/miR-34a feedback loop promotes EMT-mediated colorectal cancer invasion and metastasis. (2014, background): “However, the CRC cell lines with a mesenchymal phenotype, which consist only of tumor cells, showed elevated expression of the s–IL-6R, which is involved in IL-6 transsignal-ing (55) and is also under control of miR-34a.”
- Inflammation: The Common Pathway of Stress-Related Diseases (2017, background): “Moreover, evidence that disruption of IL-6 trans-signaling delays growth in established murine tumors demonstrates that IL-6 activities are important during neoplastic progression (Grivennikov et al., 2009; Rose-John, 2012).”
- Role of interleukin-6 in cancer progression and therapeutic resistance (2016, background): “Like sIL-6R, a soluble form of the signal transducer protein gp130 (sgp130) is also present in the circulation at relatively high concentrations during inflammation and cancer [37, 39].”
- SARS-CoV-2 infection: The role of cytokines in COVID-19 disease (2020, neutral): “It has been reported that it has regenerative and anti-inflammatory effects mediated by the conventional signaling process, although it also exerts proinflammatory effects mediated by trans-signaling, as in the case of viral infections [76].”
- A Review of SARS-CoV-2 and the Ongoing Clinical Trials (2020, background): “Hence, specific blockade of IL-6-regulated signaling pathways represents a promising approach to attenuate inflammation-associated damage [78].”