Dissecting Interleukin-6 Classic- and Trans-Signaling in Inflammation and Cancer.

Interleukin-6 is a cytokine synthesized by many cells in the human body. IL-6 binds to a membrane bound IL-6R, which is only present on hepatocytes, some epithelial cells and some leukocytes. The complex of IL-6 and IL-6R binds to the ubiquitously expressed receptor subunit gp130, which forms a homodimer and thereby initiates intracellular signaling via the JAK/STAT and the MAPK pathways. IL-6R expressing cells can cleave the receptor protein to generate a soluble IL-6R (sIL-6R), which can still bind IL-6 and can associate with gp130 and induce signaling even on cells, which do not express IL-6R. This paradigm has been called IL-6 trans-signaling whereas signaling via the membrane bound IL-6R is referred to as classic signaling. We have generated several molecular tools to differentiate between IL-6 classic- and trans-signaling and to analyze the consequence of cellular IL-6 signaling in vivo.