Rose-John S, Scheller J, Elson G, Jones SAInterleukin-6 biology is coordinated by membrane-bound and soluble receptors: role in inflammation and cancer. J Leukoc Biol 80:227-236

Biochemisches Institut, Christian-Albrechts-Universität zu Kiel, Olshausenstr. 40, D-24098 Kiel, Germany.
Journal of Leukocyte Biology (Impact Factor: 4.29). 09/2006; 80(2):227-36. DOI: 10.1189/jlb.1105674
Source: PubMed


Cytokine receptors, which exist in membrane-bound and soluble forms, bind their ligands with comparable affinity. Although most soluble receptors are antagonists and compete with their membrane-associated counterparts for the ligands, certain soluble receptors are agonists. In these cases, complexes of ligand and soluble receptor bind on target cells to second receptor subunits and initiate intracellular signaling. The soluble receptors of the interleukin (IL)-6 family of cytokines (sIL-6R, sIL-11R, soluble ciliary neurotrophic factor receptor) are agonists capable of transmitting signals through interaction with the universal signal-transducing receptor for all IL-6 family cytokines, gp130. In vivo, the IL-6/sIL-6R complex stimulates several types of cells, which are unresponsive to IL-6 alone, as they do not express the membrane IL-6R. We have named this process trans-signaling. The generation of soluble cytokine receptors occurs via two distinct mechanisms-limited proteolysis and translation-from differentially spliced mRNA. We have demonstrated that a soluble form of the IL-6 family signaling receptor subunit gp130, which is generated by differential splicing, is the natural inhibitor of IL-6 trans-signaling responses. We have shown that in many chronic inflammatory diseases, including chronic inflammatory bowel disease, peritonitis, rheumatoid arthritis, asthma, as well as colon cancer, IL-6 trans-signaling is critically involved in the maintenance of a disease state, by promoting transition from acute to chronic inflammation. Moreover, in all these models, the course of the disease can be disrupted by specifically interfering with IL-6 trans-signaling using the soluble gp130 protein. The pathophysiological mechanisms by which the IL-6/sIL-6R complex regulates the inflammatory state are discussed.

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    • "gp130 is widely distributed throughout the CNS, but IL-6 receptor distribution is more restricted. IL-6 can also produce biological effects by trans-signaling, which results from shedding of the membrane receptor to form a soluble receptor or alternative splicing of IL-6 receptor mRNA (Rose-John et al., 2006). The soluble receptor after binding IL-6 can interact with gp130 in IL-6 receptor expressing cells and in cells that normally do not express IL-6 receptor but do express gp130. "
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    • "However, IL-6 induced biological activities are largely mediated via a natural formation of an agonistic complex with soluble IL-6 receptor (sIL-6R); this complex binds gp130 and then triggers cellular responses. This activity is termed “IL-6 trans-signaling” and plays a critical role in promoting chronic inflammation and inflammation related cancer [33, 38, 39]. Thus, it would be interesting to further investigate whether blockade of IL-6 trans-signaling can prevent the development of CAC in UC. "
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    • "In regard to IL-6 signaling, this cytokine binds to its specific membrane-bound a-receptor IL-6R followed by formation of the signaling complex via a gp130 homodimer. In contrast to gp130, IL-6R is only expressed on a limited number of cell types, as there are hepatocytes, megakaryocytes and some leukocytes, namely monocytes, macrophages, B cells and subtypes of T cells [13] [14]. This fact facilitates the selective activation of definite target cells, therefore differentiating between two different signaling-pathways (Fig. 1). "
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