Interplay between interleukin-6 signaling and the vascular endothelium in cytokine storms

Interleukin-6 (IL-6) plays a crucial role in host defense against infection and tissue injuries and is a bioindicator of multiple distinct types of cytokine storms. In this review, we present the current understanding of the diverse roles of IL-6, its receptors, and its signaling during acute severe systemic inflammation. IL-6 directly affects vascular endothelial cells, which produce several types of cytokines and chemokines and activate the coagulation cascade. Endothelial cell dysregulation, characterized by abnormal coagulation and vascular leakage, is a common complication in cytokine storms. Emerging evidence indicates that a humanized anti-IL-6 receptor antibody, tocilizumab, can effectively block IL-6 signaling and has beneficial effects in rheumatoid arthritis, juvenile systemic idiopathic arthritis, and Castleman’s disease. Recent work has also demonstrated the beneficial effect of tocilizumab in chimeric antigen receptor T-cell therapy-induced cytokine storms as well as coronavirus disease 2019 (COVID-19). Here, we highlight the distinct contributions of IL-6 signaling to the pathogenesis of several types of cytokine storms and discuss potential therapeutic strategies for the management of cytokine storms, including those associated with sepsis and COVID-19. Inflammation: Stopping the storm Blocking interleukin-6, a signaling molecule known as a cytokine, may help in treatment of both chronic and acute inflammation. IL-6 is part of a healthy immune response, but is also implicated in chronic inflammatory diseases such as rheumatoid arthritis and in ‘cytokine storms’, when the inflammatory response spirals out of control. Sujin Kang and Tadamitsu Kishimoto at Osaka University in Japan have reviewed the roles IL-6 plays in chronic and acute inflammation, and how an antibody to the IL-6 receptor, tocilizumab, shows therapeutic potential. They report that tocilizumab successfully blocks IL-6 signaling and has beneficial effects against rheumatoid and juvenile systemic idiopathic arthritis, and other chronic inflammatory conditions. Tocilizumab has also been shown to suppress cytokine storms brought on by CAR-T cell therapy and COVID-19. These results pave the way for better treatments for inflammatory conditions.