ADAM17 orchestrates pro- and anti- inflammatory cytokine activities in inflammation and cancer

Cytokine 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 TNFα and ligands of the EGF-R. We generated hypomorphic ADAM17 mice, which have undetectable ADAM17 protein levels in all tissues but which are still viable. Using these mice in different inflammation models we could show that activation of ADAM17 has different effects on the activation of the immune response as well as on induction of regenerative responses [2, 3]. Therefore, ADAM17 is a molecular switch of inflammatory and regenerative responses of the body to stress [3]. Using the sgp130Fc protein or sgp130Fc transgenic mice we further demonstrate that in several chronic inflammatory diseases and cancers including inflammatory bowel disease, peritonitis, rheumatoid arthritis, colon cancer, ovarian cancer and pancreatic cancer, 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 promising novel therapeutic agent for the treatment of chronic inflammatory diseases and cancer [1, 4-6]. References 1. Jones SA, Scheller J, Rose-John S (2011) J Clin Invest, in press. 2. Chalaris A, Adam N, Sina C, Rosenstiel P, Lehmann J, Schirmacher P, Hartmann D, Cichy J, Gavrilova O, Schreiber S, Jostock T, Matthews V, Häsler R, Becker C, Neurath MF, Reiß K, Saftig P, Scheller J, Rose-John S (2010) J Exp Med 207: 1617-1624. 3. Scheller J, Chalaris A, Garbers C, Rose-John S (2011) Trends Immunol, in press. 4. Lesina M, Kurkowski MU, Ludes K, Rose-John S, Treiber M, Klöppel G, Yoshimura A, Reindl W, Sipos B, Akira S, Schmid RM, Algül H (2011) Cancer Cell 19: 456-469. 5. Schiechl G, Bauer B, Fuss IJ, Lang SA. Moser C, Rose-John S, Neurath MF, Geissler E, Schlitt HJ, Strober W, Fichtner-Feigl S (2011) J Clin Invest 121: 1692-1708. 6. Lo C-W, Chen MW, Hsiao M, Wang S, Chen C-A, Hsiao S-M, Chang J-S, Lai T-C, Rose-John S, Kuo M-L, Wei L-H (2011) Cancer Res 71: 424-34. L1.2