ADAM17 AS A MASTERSWITCH IN THE REGULATION OF INFLAMMATION AND CANCER

S. Rose-John, A. ChalarisBiochemistry, University of Kiel, Kiel, GermanyCytokine receptors exist in membrane bound and soluble form. While most soluble receptors are antagonists, some soluble receptors are agonists like soluble receptors of the gp130 cytokine family. In vivo, the IL-6/soluble IL-6R complex stimulates several types of target cells not stimulated by IL-6 alone, since they do not express the membrane bound IL-6R. This process has been named trans-signaling [1]. We have shown that soluble gp130 is the natural inhibitor of IL-6/soluble IL-6R complex responses. The recombinant soluble gp130 protein is a molecular tool to discriminate between gp130 responses via membrane bound and soluble IL-6R responses. We have constructed a fusion of soluble gp130 and the Fc portion of human IgG1. This sgp130Fc protein proved to be efficient in blocking responses via the IL-6/soluble IL-6R complex without affecting IL-6 responses, which are mediated via the membrane bound IL-6R [1]. The soluble IL-6R is mostly generated by proteolysis of the IL-6R transmembrane protein. Shedding of the IL-6R is mediated by the metalloprotease ADAM17, which is also responsible for the cleavage of TNF-α and ligands of the EGF-R. Consequently, activation of ADAM17 has different effects on the activation of the immune response as well as on induction of regenerative responses [2,3]. We have generated hypomorphic ADAM17 mice which express undetectable levels of ADAM17 in all tissues [2]. These mice have been used to address the role of ADAM17 in animal models of inflammation and cancer. Addressing the role of IL-6, we show that the extent of IL-6 trans-signaling in chronic inflammatory diseases and cancer is controlled by the soluble IL-6R. Using the sgp130Fc protein or sgp130Fc transgenic mice we demonstrate that in several chronic inflammatory diseases and cancers including inflammatory bowel disease, peritonitis, rheumatoid arthritis, colon cancer, ovarian cancer and pancreatic cancer, that IL-6 trans-signaling via the soluble IL-6R is a 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 [1, 4-9]. References: 1. Jones et al (2011) J Clin Invest 121: 3375-3383 2. Chalaris et al (2010) J Exp Med 207: 1617-1624 3. Scheller et al (2011) Trends Immunol 32: 380-387 4. Barkhausen et al Crit Care Med 39: 1407-1413 5. Greenhill et al (2011) J Immunol, 186: 1199-208 6. Lesina et al (2011) Cancer Cell 19: 456-469 7. Schiechl et al (2011) J Clin Invest 121: 1692-1708 8. Lo et al (2011) Cancer Res 71: 424-34 9. Schuett et al (2012) Arterioscler Thromb Vasc Biol32: 281-290 Disclosure of Interest: S. Rose-John Shareholder of: Conaris Research Institute, A. Chalaris: None DeclaredCitation: Annals of the Rheumatic Diseases, volume 71, supplement 3, year 2012, page 6Session: Meet the ADAM's family: ADAM, MMP's, ADAMTS (Speaker Presentations )