Interleukin-6: from identification of the cytokine to development of targeted treatments

Abstract

Interleukin-6 (IL-6) was identified based on extensive research conducted simultaneously on a variety of topics ranging from hepatocyte production of acute-phase proteins to plasmacytoma growth. IL-6 is a cytokine produced by a broad array of cell types and can exert its effects on virtually all cells. IL-6 can induce cell signaling not only via the classic pathway involving the transmembrane receptor IL-6Rα (restricted cellular expression) associated with gp130 (ubiquitous and responsible for signal transmission), but also via the soluble receptor IL-6Rα, which binds to IL-6 and induces a signal mediated by the ubiquitous gp130 molecule (transsignaling). IL-6 is deregulated in many inflammatory and autoimmune diseases, including rheumatoid arthritis (RA). By virtue of its multiple effects, IL-6 is involved in the various phases of RA development, including the acute phase, immuno-inflammatory phase, and destructive phase. IL-6 has an impact on the many pathogenic factors identified in RA and, consequently, holds promise for targeted treatments. However, anti-IL-6 monoclonal antibodies evaluated as IL-6 antagonists, instead, increased the half-life of the cytokine. In contrast, monoclonal antibody (tocilizumab) to transmembrane and soluble IL-6Rα has been found effective in patients with RA. Tocilizumab is now indicated for the treatment of adults with RA who have failed at least one synthetic disease-modifying antirheumatic drug or TNFα antagonist.