Interleukin-6: from identification of the cytokine to development of targeted treatments.
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.
Assier
Eric
E
Li2P EA4222, PRES université Paris-Cité (Paris-13), 74, rue Marcel-Cachin, 93017 Bobigny, France. eric.assier@univ-paris13.fr
Boissier
Marie-Christophe
MC
Dayer
Jean-Michel
JM
D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use; D061067:Antibodies, Monoclonal, Humanized; D018501:Antirheumatic Agents / Q000276:immunology / Q000627:therapeutic use; D001172:Arthritis, Rheumatoid / Q000188:drug therapy / Q000276:immunology / Q000378:metabolism; D050822:Cytokine Receptor gp130 / Q000276:immunology / Q000378:metabolism; D004195:Disease Models, Animal; D006801:Humans; D015850:Interleukin-6 / Q000302:isolation & purification* / Q000502:physiology*; D053698:Interleukin-6 Receptor alpha Subunit / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D058990:Molecular Targeted Therapy; D015398:Signal Transduction; D000093242:Interleukin-6 Inhibitors
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D018501:Antirheumatic Agents; D050822:Cytokine Receptor gp130; D015850:Interleukin-6; D053698:Interleukin-6 Receptor alpha Subunit; D000093242:Interleukin-6 Inhibitors; C502936:tocilizumab