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.
Rose-John
Stefan
S
Biochemisches Institut, Christian-Albrechts-Universität zu Kiel, Germany.
Schooltink
Heidi
H
D000818:Animals; D016207:Cytokines / Q000378:metabolism*; D006801:Humans; D007249:Inflammation / Q000150:complications*; D015850:Interleukin-6 / Q000378:metabolism*; D009369:Neoplasms / Q000209:etiology / Q000517:prevention & control*; D019947:Receptors, Interleukin-6 / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000138:chemical synthesis / Q000378:metabolism / Q000627:therapeutic use; D015398:Signal Transduction / Q000502:physiology*
D016207:Cytokines; D015850:Interleukin-6; D019947:Receptors, Interleukin-6; D011993:Recombinant Fusion Proteins