SEMINAR: ADAM17 in the Regulation of Inflammation and Cancer

Professor Stefan Rose-John is the Director of the Department of Biochemistry at the Christian-Albrechts-University, Kiel, Germany. He has authored 320 Original Publications and has a current H-index of 72. Over the last 25 years, his laboratory has focused on understanding the molecular biology of cytokines. Using structure-function analysis approaches, his group has defined the binding sites of interleukin-6 and its two receptor subunits, interleukin-6-receptor and gp130. This has enabled him to build the first molecular model of the interleukin-6 receptor complex and was the starting point for the construction of various designer cytokines, which have considerably higher specific biologic activity than the natural cytokines. A second aspect of his work has started with the discovery of a naturally occurring proteolytic cleavage of the interleukin-6 receptor, which leads to the generation of a soluble interleukin-6 receptor. His laboratory has discovered that the complex of soluble interleukin-6-receptor and interleukin-6 stimulates cells, which express the signal transducing receptor subunit gp130 but not the ligand binding subunit interleukin-6 receptor. In the absence of the sIL-6R such cells do not respond to IL-6. This process has been termed 'transsignaling'. Over the past 10 years, his group has shown that 'trans-signaling' is important for the regulation of cellular differentiation and of apoptosis and has a prominent role in inflammation, neuronal survival, hematopoiesis, and tumor defense. His team is currently developing the concept that the triggering of 'transsignaling' is an emergency reaction of the human immune system and that disruption of 'trans-signaling' can be used therapeutically for the treatment of chronic inflammatory diseases and cancer. Indeed, one cytokine antagonist, which – in animal models – has proven effective in blocking chronic inflammatory diseases such as Crohn’s diseases, Rheumatoid Arthritis and inflammatory colon cancer, is now tested in Phase I clinic trials since June 2013.