Therapeutic targeting of IL-6 trans-signaling.

Interleukin-6 (IL-6) is a cytokine, which is involved in innate and acquired immunity, in neural cell maintenance and in metabolism. IL-6 can be synthesized by many different cells including myeloid cells, fibroblasts, endothelial cells and lymphocytes. The synthesis of IL-6 is strongly stimulated by Toll like receptors and by IL-1. Therefore, IL-6 levels in the body are high during infection and inflammatory processes. Moreover, IL-6 is a prominent growth factor of tumor cells and plays a major role in inflammation associated cancer. On target cells, IL-6 binds to an IL-6 receptor, which is not signaling competent. The complex of IL-6 and IL-6 receptor associate with a second receptor subunit, glycoprotein gp130, which dimerizes and initiates intracellular signaling. Cells, which do not express the IL-6 receptor are not responsive to IL-6. They can, however, be stimulated by the complex of IL-6 and a soluble form of the IL-6 receptor, which is generated by limited proteolysis and to a lesser extent by translation from an alternatively spliced mRNA. This process has been named IL-6 trans-signaling. This review article will explain the biology of IL-6 trans-signaling and the specific inhibition of this mode of signaling, which has been recognized to be fundamental in inflammation and cancer.