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

Exp Mol Med. 2021 Jul;53(7):1116-1123. doi: 10.1038/s12276-021-00649-0. Epub 2021 Jul 12.


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.

Publication types

  • Review

MeSH terms

  • Antibodies, Monoclonal, Humanized / immunology
  • Antibodies, Monoclonal, Humanized / therapeutic use*
  • COVID-19 / genetics
  • COVID-19 / immunology
  • COVID-19 / pathology
  • COVID-19 / prevention & control*
  • Cytokine Release Syndrome / genetics
  • Cytokine Release Syndrome / immunology
  • Cytokines / genetics
  • Cytokines / metabolism
  • Endothelium, Vascular / immunology
  • Humans
  • Interleukin-6 / antagonists & inhibitors
  • Interleukin-6 / genetics*
  • Interleukin-6 / immunology
  • Receptors, Interleukin-6 / antagonists & inhibitors
  • Receptors, Interleukin-6 / genetics*
  • Receptors, Interleukin-6 / immunology
  • SARS-CoV-2 / immunology
  • SARS-CoV-2 / pathogenicity
  • Sepsis / genetics
  • Sepsis / immunology
  • Sepsis / pathology
  • Sepsis / prevention & control


  • Antibodies, Monoclonal, Humanized
  • Cytokines
  • Interleukin-6
  • Receptors, Interleukin-6
  • tocilizumab