Local and systemic effects of interleukin-6 (IL-6) in inflammation and cancer

Interleukin-6 (IL-6) is an inflammatory cytokine, the level of which is highly elevated in most, if not all, inflammatory states. IL-6 triggers cell type-specific responses and acts on target cells via a specific interleukin-6 receptor (IL-6R), which, together with IL-6, binds to and induces the dimerization of a second receptor subunit, gp130. IL-6 also binds to soluble IL-6R, and this complex interacts with gp130, regardless of IL-6R expression. This allows cells that do not express IL-6R and would be otherwise insensitive to IL-6 to respond to it. We have generated a constitutively active version of gp130 by forced leucine-zipper-mediated dimerization, named L-gp130. Once inserted into the Rosa26 locus of mice, L-gp130 can be activated in a cell-autonomous manner by crossing these mice with any Cre-recombinase transgenic mouse strain. Activation of gp130 in hepatocytes produced liver-specific effects such as the induction of acute-phase proteins, but it also had profound systemic effects on the immune system. Such local and systemic effects of interleukin-6 will be reviewed.