Interleukin-6: From basic biology to selective blockade of pro-inflammatory activities

• The IL-6 receptor can be shed from the cellular membrane by the protease ADAM17.
• The complex of IL-6 and IL-6 receptor induces signaling on cells only expressing gp130, a process has been named trans-signaling.
• IL-6 trans-signaling can be specifically blocked by soluble gp130.
• IL-6 trans-signaling is pro-inflammatory whereas IL-6 signaling via the membrane bound IL-6 receptor is regenerative and protects from bacterial infections.
• A soluble gp130Fc protein has been developed as an anti-inflammatory drug, which is currently tested as in phase I clinical trials.

Cytokines receptors exist in membrane bound and soluble form. A soluble form of the human IL-6R is generated by limited proteolysis and alternative splicing. The complex of IL-6 and soluble IL-6R stimulates target cells not stimulated by IL-6 alone, since they do not express the membrane bound IL-6R. We have named this process trans-signaling. Soluble gp130 is the natural inhibitor of IL-6/soluble IL-6R complex responses. Recombinant soluble gp130 protein is a molecular tool to discriminate between gp130 responses via membrane bound and soluble IL-6R responses. Neutralizing monoclonal antibodies for global blockade of IL-6 signaling and the sgp130Fc protein for selective blockade of IL-6 trans-signaling have been used in several animal models of human diseases. Using the sgp130Fc protein or sgp130Fc transgenic mice we demonstrate in models of inflammatory bowel disease, peritonitis, rheumatoid arthritis, atherosclerosis pancreatitis, colon cancer, ovarian cancer and pancreatic cancer, that IL-6 trans-signaling via the soluble IL-6R is the crucial step in the development and the progression of the disease. Therefore, sgp130Fc is a novel therapeutic agent for the treatment of chronic inflammatory diseases and cancer and it undergoes phase I clinical trials as an anti-inflammatory drug since June 2013.