Biology Reference
In-Depth Information
Chapter 4
The Regenerative Activity of Interleukin-6
Eithan Galun and Stefan Rose-John
Abstract
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 pro-
teins, 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, kid-
ney, and other tissues and therefore will be a novel therapeutic approach in regenerative medicine.
Key words gp130, Inflammation, Interleukin-6, Interleukin-6-receptor, Regeneration, Shedding,
Soluble interleukin-6-receptor, STAT3, Stem cells
1
Introduction
Interleukin-6 (IL-6) is a four helical cytokine of 184 amino acid
residues ( 1, 2 ). IL-6 binds to a cell surface receptor called IL-6R,
which is a type I transmembrane protein with no intrinsic signaling
capacity ( 3 ). When IL-6 becomes bound to IL-6R, the complex
associates with a second protein called gp130 ( 4 ). Upon binding
to the IL-6/IL-6R complex, gp130 dimerizes and initiates intrac-
ellular signaling (Fig. 1 ) ( 5, 6 ). It turned out that gp130 is not
only the signal transducing receptor subunit of IL-6R, but is also
part of the receptor complexes for the cytokines Interleukin-11
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