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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\u2019s 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.<\/jats:p>","DOI":"10.1038\/s12276-021-00649-0","type":"journal-article","created":{"date-parts":[[2021,7,12]],"date-time":"2021-07-12T05:03:05Z","timestamp":1626066185000},"page":"1116-1123","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":374,"title":["Interplay between interleukin-6 signaling and the vascular endothelium in cytokine storms"],"prefix":"10.1038","volume":"53","author":[{"given":"Sujin","family":"Kang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tadamitsu","family":"Kishimoto","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2021,7,12]]},"reference":[{"key":"649_CR1","doi-asserted-by":"publisher","first-page":"347","DOI":"10.1093\/intimm\/dxq030","volume":"22","author":"T Kishimoto","year":"2010","unstructured":"Kishimoto, T. 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