Blocking only the bad side of IL-6 in inflammation and cancer

Abstract

Interleukin-6 (IL-6) is considered an inflammatory cytokine, which is involved not only in most inflammatory states but it also plays a prominent role in inflammation associated cancers. The response of cells to the cytokine strictly depends on the presence of the IL-6 receptor (IL-6R),which presents IL-6 to the signal transducing receptor subunit gp130, which is expressed on all cells of the body. The expression of IL-6R is limited to some cells, which are therefore IL-6 target cells. The IL-6R can be cleaved by proteases and the thus generated soluble IL-6R (sIL-6R) still binds the ligand IL-6. The complex of IL-6 and sIL-6R can bind to gp130 on any cell, induce dimerization of gp130 and intracellular signaling. This process has been named IL-6 trans-signaling. A fusion protein of soluble gp130 with the constant portion of human IgG1 (sgp130Fc) turned out to be a potent and specific inhibitor of IL-6 trans-signaling. In many animal models of human diseases the significance of IL-6 trans-signaling has been analyzed. It turned out that the activities of IL-6 mediated by the sIL-6R are the pro-inflammatory activities of the cytokine whereas activities of IL-6 mediated by the membrane-bound IL-6R are rather protective and regenerative. The sgp130Fc protein has recently been developed into a biologic. The possible consequences of a specific IL-6 trans-signaling blockade is discussed in the light of the recent successfully concluded phase II clinical trials in patients with inflammatory bowel disease.

Keywords: Classic-signaling; Interleukin-6; Receptor; Shedding; Trans-signaling.