The regenerative activity of interleukin-6.

Interleukin-6 (IL-6) is a cytokine which is involved in many inflammatory processes and in the development of cancer. In addition, IL-6 has been shown to be important for the induction of hepatic acute-phase proteins, for the regeneration of the liver and for the stimulation of B-cells. IL-6 binds to a transmembrane IL-6 receptor (IL-6R), which is present on hepatocytes and some leukocytes. The complex of IL-6 and IL-6R associates with a second protein, gp130, which is expressed on all cells of the body. Since neither IL-6 nor IL-6R has a measurable affinity for gp130, cells, which do not express IL-6R, are not responsive to the cytokine IL-6. It could be shown, however, that a naturally occurring soluble IL-6R (sIL-6R) in complex with IL-6 can bind to gp130 on cells with no IL-6R expression. Therefore, cells shedding the sIL-6R render cells, which only express gp130, responsive to the cytokine. This process has been called trans-signaling. In the present chapter, we summarize the known activities of IL-6 with a special emphasis on regenerative activities, which often depend on the sIL-6R. A designer cytokine called Hyper-IL-6, which is a fusion protein of IL-6 and the sIL-6R, can mimic IL-6 trans-signaling responses in vitro and in vivo with considerably higher efficacy than the combination of the natural proteins IL-6 and sIL-6R. We present recent examples from animal models in which the therapeutic potential of Hyper-IL-6 has been evaluated. We propose that Hyper-IL-6 can be used to induce potent regeneration responses in liver, kidney, and other tissues and therefore will be a novel therapeutic approach in regenerative medicine.