Interleukin 6 (IL-6), a prototypical cytokine with redundant and pleiotropic activities, contributes to host defense against infections and tissue injuries by inducing the acute-phase response and activating immune responses and hematopoiesis. However, excessive or continuous IL-6 production plays a pathological role in an acute severe life-threatening complication, the so-called cytokine storm, and in various chronic autoimmune inflammatory diseases.
As described elsewhere, the immediate and transient expression of IL-6 contributes to host defense against infections and tissue injuries. However, deregulated excessive IL-6 synthesis during this protective process or persistent IL-6 production leads to the development of a severe acute life-threatening complication, the so-called cytokine storm or chronic autoimmune inflammatory diseases, respectively. The association of IL-6 with disease development was first demonstrated in a case of benign heart tumor, cardiac myxoma. The cultured fluid from the myxoma tissue of a patient, who had presented with fever, polyarthritis, an elevated CRP level, anemia, and hypergammaglobulinemia with positivity for anti-nuclear factor, was found to contain a large quantity of IL-6. Subsequently, excessive IL-6 expression was also detected in the synovial fluids of rheumatoid arthritis (RA), swollen lymph nodes of Castleman's disease, myeloma cells, and peripheral blood cells or infiltrating cells in tissues involved in various other autoimmune inflammatory diseases. The extent of the elevation of the serum IL-6 level depends on the particular disease and its disease severity, but in cytokine storms such as those associated with septic shock, the concentration can reach as high as the microgram per milliliter level.
In view of the pathological role of IL-6 in various autoimmune inflammatory diseases, IL-6 targeting was evaluated as a novel therapeutic strategy against these diseases. Tocilizumab, a humanized anti-IL-6R monoclonal Ab of the IgG1 class, was generated by grafting the complementarity-determining regions of a mouse anti-human IL-6R Ab onto human IgG1. This Ab can block IL-6- mediated signal transduction by inhibiting IL-6 binding to both transmembrane IL-6R and sIL-6R. Numerous worldwide clinical trials verified the outstanding efficacy and tolerable safety of tocilizumab, leading to its current approval for the treatment of RA in more than 130 countries; systemic juvenile idiopathic arthritis (sJIA) in Japan, India, the USA, and the EU; and polyarticular JIA and Castleman's disease in Japan and India.
Although fundamental research on the IL-6-mediated signaling pathway was able to solve the long-standing mystery regarding why cytokines exhibit redundant and pleiotropic activity, another mystery persists regarding why IL-6 is excessively or continuously expressed in various diseases. Accurate and detailed analyses of the proteins such as Arid5a and Regnase-1 and miRs that regulate IL-6 synthesis will be helpful in solving this mystery. Clarifi cation of the mechanism(s) involved will inspire the identifi cation of more specifi c target molecules and investigations into the pathogenesis of specifi c diseases.
Kishimoto T, et al. IL-6: A New Era for the Treatment of Autoimmune Inflammatory Diseases[M]//Innovative Medicine. Springer Japan, 2015: 131-147.