The Biology Of Interleukin-6, A Major Target In Anti-Inflammatory Therapies

Interleukin-6 (IL-6) belongs to the four-helical cytokine family. The cytokine on target cells binds to the membrane-bound IL-6 receptor. The complex of IL-6 and IL-6 receptor associates with the membrane protein, glycoprotein 130 (gp130), leading to initiation of intracellular signaling via the JAK/STAT and Ras-Raf-MAPK signaling pathways. The signaling protein gp130 is a component of cytokines of the so-called gp130 family. The IL-6 receptor is only expressed on hepatocytes and some leukocytes, whereas gp130 is expressed on all cells of the body. It was shown that a soluble form of the IL-6 receptor can bind the ligand IL-6 and this soluble complex can bind to gp130 in the absence of membrane-bound IL-6 receptor. This signaling mode has been called trans-signaling. In this article, we argue that biologic activities mediated via the soluble IL-6 receptor are mainly proinflammatory, whereas activities via the membrane-bound IL-6 receptor are rather protective and regenerative. The consequences of this new paradigm for the therapeutic blockade of IL-6 signaling in autoimmune diseases are discussed.