Cytokines are a therapeutic target for the prevention of inflammation-induced cancers.

Interleukin-6 (IL-6) is an inflammatory cytokine with a well-documented role in cancer. The cytokine binds to a membrane-bound IL-6 receptor (IL-6R) and this complex associates with two molecules of the signal transducing protein gp130, initiating intracellular signaling. Whereas gp130 is expressed on all cells of the body, the IL-6R is only found on some cells, mainly hepatocytes and several leukocytes. Cells, which only express gp130 and no IL-6R, cannot respond to IL-6. We have shown that the IL-6R exists as a soluble protein generated by limited proteolysis of the membrane-bound receptor or by translation from an alternatively spliced mRNA. The complex of soluble IL-6R (sIL-6R) and IL-6 can bind to gp130 on cells that lack the membrane-bound IL-6R and trigger gp130 signaling. We have named this process trans-signaling. We review data that show that IL-6 uses classical signaling via the membrane-bound receptor and trans-signaling via the soluble receptor in physiological and pathophysiological situations. We have developed designer cytokines, which specifically enhance or inhibit IL-6 trans-signaling. These designer cytokines have been shown to be extremely useful in therapeutic applications such as blockade of chronic inflammation and cancer.