I13 The pro-inflammatory activities of interleukin-6 are mediated by trans-signaling

Abstract

Cytokines and cytokine receptors exist in membrane bound and soluble form. Membrane bound cytokinesneed to cleaved in order to become systemically available. While most soluble receptors are antagonists, some areagonists like the soluble IL-6 receptors. In vivo, the IL-6/soluble IL-6R complex stimulates several types of target cells notstimulated by IL-6 alone, since they do not express the membrane bound IL-6R. This process has been named transsignaling[1]. We have shown that 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 boundand soluble IL-6R responses [1]. The soluble IL-6R is mostly generated by proteolysis of the IL-6R transmembraneprotein. Shedding of the IL-6R is mediated mainly by the metalloprotease ADAM17, which is also responsible for thecleavage of TNFa and ligands of the EGF-R. Consequently, activation of ADAM17 has different effects on the activationof the immune response as well as on induction of regenerative responses [2,3]. We used neutralizing monoclonal antibodies for global blockade of IL-6 signaling and the sgp130Fc protein forselective blockade of IL-6 trans-signaling in several animal models of human diseases. We could show that inhibition of IL-6 trans-signaling was beneficial in a sepsis model. Also bacterial infectionmodels suggest a different outcome of global blockade of IL-6 as compared to selective IL-6 trans-signaling inhibition [4].Conclusion: The extent of inflammation is controlled by trans-signaling via the soluble IL-6R. Using the sgp130Fcprotein or sgp130Fc transgenic mice we demonstrate in several chronic inflammatory diseases and cancers includinginflammatory bowel disease, peritonitis, rheumatoid arthritis, atherosclerosis, colon cancer, ovarian cancer andpancreatic cancer, that IL-6 trans-signaling via the soluble IL-6R is a crucial step in the development and the progressionof the disease. Therefore, sgp130Fc is a novel therapeutic agent for the treatment of chronic inflammatory diseases andcancer [5-7].