On target cells IL-6 first binds to the IL-6 receptor (IL-6R). The complex of IL-6 and IL-6R associates with the signaltransducing membrane protein gp130, thereby inducing its dimerization and initiation of signaling. gp130 is expressed by all cells in the body whereas IL-6R is mainly expressed by hepatocytes, monocytes/macrophages and lymphocytes. A naturally occurring soluble form of the IL-6R (sIL-6R), which has been found in various body fluids, is generated by two independent mechanisms, limited proteolysis of the membrane protein and translation from an alternatively spliced mRNA². Interestingly, the sIL-6R together with IL-6 stimulates cells which only express gp 130³’⁴a process which has been named transsignaling²’⁵. Recently, it has been shown that the sIL-6R strongly sensitizes target cells⁶. Early hematopoietic progenitor cells⁵’⁷many neural cells“, smooth muscle cells and endothelial cells’¹among others, are only responsive to IL-6 in the presence of sIL-6R¹².