Interleukin‐6 Trans‐Signalling in Chronic Inflammation and Cancer

• Published in: Scandinavian journal of immunology Vol. 63; no. 5; pp. 321 - 329
• Main Authors: Scheller, J., Ohnesorge, N., Rose‐John, S.
• Format: Journal Article
• Language: English
• Published: Oxford, UK; Malden, USA Blackwell Publishing Ltd 01.05.2006; Wiley Subscription Services, Inc
• Subjects: Animals; Cell Membrane - immunology; Cell Membrane - metabolism; Chronic Disease; Colonic Neoplasms - immunology; Humans; Inflammation - immunology; Interleukin-6 - genetics; Interleukin-6 - metabolism; Interleukin-6 - physiology; Receptors, Interleukin-6 - genetics; Receptors, Interleukin-6 - metabolism; Receptors, Interleukin-6 - physiology; Signal Transduction; Solubility
• ISSN: 0300-9475; 1365-3083
• DOI: 10.1111/j.1365-3083.2006.01750.x

Interleukin‐6 (IL‐6) is a cytokine, which plays an important role in many chronic inflammatory diseases. IL‐6 belongs to a family of 10 cytokines, which all act via receptor complexes containing the cytokine receptor subunit gp130. On cells, IL‐6 first binds to a specific membrane‐bound IL‐6R and the complex of IL‐6 and IL‐6R interacts with gp130 leading to signal initiation. Whereas gp130 is widely expressed throughout the body, the IL‐6R is only found on some cells including hepatocytes and some leucocytes. A soluble form of the IL‐6R is an agonist capable of transmitting signals through interaction with the gp130 protein. In vivo, the IL‐6/soluble IL‐6R complex stimulates several types of target cells, which are unresponsive to IL‐6 alone, as they do not express the membrane‐bound IL‐6R. We have named this process trans‐signalling. We provided evidence that a soluble form of the IL‐6 family signalling receptor subunit gp130 is the natural inhibitor of IL‐6 trans‐signalling responses. We showed that in chronic inflammatory diseases such as inflammatory bowel disease, peritonitis, rheumatoid arthritis, asthma as well as in colon cancer, IL‐6 trans‐signalling is critically involved in the maintenance of the disease state. Moreover, in all these animal models, the progression of the disease can be interrupted by specifically interfering with IL‐6 trans‐signalling using recombinant‐soluble gp130Fc protein. The pathophysiologic mechanisms by which the IL‐6/soluble IL‐6R complex perpetuates the inflammatory state are discussed.