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Tytuł pozycji:

IL-6 trans-signaling induces plasminogen activator inhibitor-1 from vascular endothelial cells in cytokine release syndrome.

Tytuł :
IL-6 trans-signaling induces plasminogen activator inhibitor-1 from vascular endothelial cells in cytokine release syndrome.
Autorzy :
Kang S; Department of Immune Regulation, Immunology Frontier Research Center, Osaka University, Suita, Osaka 565-0871, Japan.
Tanaka T; Medical Affairs Bureau, Osaka Habikino Medical Center, Osaka 583-8588, Japan.
Inoue H; Department of Immune Regulation, Immunology Frontier Research Center, Osaka University, Suita, Osaka 565-0871, Japan.
Ono C; Department of Molecular Virology, Research Institute for Microbial Diseases, Osaka University, Suita, Osaka 565-0871, Japan.
Hashimoto S; Department of Clinical Laboratory, Osaka Habikino Medical Center, Osaka 583-8588, Japan.
Kioi Y; Department of Immune Regulation, Immunology Frontier Research Center, Osaka University, Suita, Osaka 565-0871, Japan.
Matsumoto H; Department of Traumatology and Acute Critical Medicine, Osaka University Graduate School of Medicine, Osaka University, Suita, Osaka 565-0871, Japan.
Matsuura H; Department of Traumatology and Acute Critical Medicine, Osaka University Graduate School of Medicine, Osaka University, Suita, Osaka 565-0871, Japan.
Matsubara T; Department of Traumatology and Acute Critical Medicine, Osaka University Graduate School of Medicine, Osaka University, Suita, Osaka 565-0871, Japan.
Shimizu K; Department of Traumatology and Acute Critical Medicine, Osaka University Graduate School of Medicine, Osaka University, Suita, Osaka 565-0871, Japan.
Ogura H; Department of Traumatology and Acute Critical Medicine, Osaka University Graduate School of Medicine, Osaka University, Suita, Osaka 565-0871, Japan.
Matsuura Y; Department of Molecular Virology, Research Institute for Microbial Diseases, Osaka University, Suita, Osaka 565-0871, Japan.
Kishimoto T; Department of Immune Regulation, Immunology Frontier Research Center, Osaka University, Suita, Osaka 565-0871, Japan; .
Pokaż więcej
Źródło :
Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 2020 Sep 08; Vol. 117 (36), pp. 22351-22356. Date of Electronic Publication: 2020 Aug 21.
Typ publikacji :
Journal Article; Research Support, Non-U.S. Gov't
Język :
English
Imprint Name(s) :
Original Publication: Washington, DC : National Academy of Sciences
MeSH Terms :
Signal Transduction*
Cytokine Release Syndrome/*metabolism
Endothelial Cells/*metabolism
Interleukin-6/*metabolism
Plasminogen Activator Inhibitor 1/*metabolism
Adult ; Aged ; Antibodies, Monoclonal, Humanized/therapeutic use ; Betacoronavirus ; Burns/metabolism ; Burns/pathology ; Cells, Cultured ; Coronavirus Infections/drug therapy ; Coronavirus Infections/metabolism ; Coronavirus Infections/pathology ; Cytokine Release Syndrome/drug therapy ; Cytokine Release Syndrome/pathology ; Cytokines/blood ; Cytokines/metabolism ; Endothelial Cells/drug effects ; Female ; Humans ; Inflammation ; Interleukin-6/blood ; Male ; Middle Aged ; Pandemics ; Plasminogen Activator Inhibitor 1/blood ; Pneumonia, Viral/drug therapy ; Pneumonia, Viral/metabolism ; Pneumonia, Viral/pathology ; Receptors, Interleukin-6/antagonists & inhibitors ; Receptors, Interleukin-6/metabolism ; Respiratory Distress Syndrome, Adult/metabolism ; Respiratory Distress Syndrome, Adult/pathology ; Sepsis/metabolism ; Sepsis/pathology
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Contributed Indexing :
Keywords: COVID-19*; IL-6*; cytokine release syndrome*; endothelial cell*; tocilizumab*
Substance Nomenclature :
0 (Antibodies, Monoclonal, Humanized)
0 (Cytokines)
0 (IL6 protein, human)
0 (IL6R protein, human)
0 (Interleukin-6)
0 (Plasminogen Activator Inhibitor 1)
0 (Receptors, Interleukin-6)
0 (SERPINE1 protein, human)
I031V2H011 (tocilizumab)
SCR Disease Name :
COVID-19
Entry Date(s) :
Date Created: 20200823 Date Completed: 20200917 Latest Revision: 20200924
Update Code :
20201023
PubMed Central ID :
PMC7486751
DOI :
10.1073/pnas.2010229117
PMID :
32826331
Czasopismo naukowe
Cytokine release syndrome (CRS) is a life-threatening complication induced by systemic inflammatory responses to infections, including bacteria and chimeric antigen receptor T cell therapy. There are currently no immunotherapies with proven clinical efficacy and understanding of the molecular mechanisms of CRS pathogenesis is limited. Here, we found that patients diagnosed with CRS from sepsis, acute respiratory distress syndrome (ARDS), or burns showed common manifestations: strikingly elevated levels of the four proinflammatory cytokines interleukin (IL)-6, IL-8, monocyte chemotactic protein-1 (MCP-1), and IL-10 and the coagulation cascade activator plasminogen activator inhibitor-1 (PAI-1). Our in vitro data indicate that endothelial IL-6 trans-signaling formed an inflammation circuit for robust IL-6, IL-8, and MCP-1 production and promoted PAI-1 production; additionally, an IL-6 signaling blockade by the human monoclonal antibody tocilizumab blunted endothelial cell activation. Plasma from severe COVID-19 patients similarly exhibited increased IL-6, IL-10, and MCP-1 levels, but these levels were not as high as those in patients with CRS from other causes. In contrast, the PAI-1 levels in COVID-19 patients were as highly elevated as those in patients with bacterial sepsis or ARDS. Tocilizumab treatment decreased the PAI-1 levels and alleviated critical illness in severe COVID-19 patients. Our findings suggest that distinct levels of cytokine production are associated with CRS induced by bacterial infection and COVID-19, but both CRS types are accompanied by endotheliopathy through IL-6 trans-signaling. Thus, the present study highlights the crucial role of IL-6 signaling in endothelial dysfunction during bacterial infection and COVID-19.
(Copyright © 2020 the Author(s). Published by PNAS.)

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