PMID- 32826331
OWN - NLM
STAT- MEDLINE
DCOM- 20200917
LR  - 20210512
IS  - 1091-6490 (Electronic)
IS  - 0027-8424 (Print)
IS  - 0027-8424 (Linking)
VI  - 117
IP  - 36
DP  - 2020 Sep 8
TI  - IL-6 trans-signaling induces plasminogen activator inhibitor-1 from vascular 
      endothelial cells in cytokine release syndrome.
PG  - 22351-22356
LID - 10.1073/pnas.2010229117 [doi]
AB  - 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.
CI  - Copyright (c) 2020 the Author(s). Published by PNAS.
FAU - Kang, Sujin
AU  - Kang S
AUID- ORCID: 0000-0001-5086-1405
AD  - Department of Immune Regulation, Immunology Frontier Research Center, Osaka 
      University, Suita, Osaka 565-0871, Japan.
FAU - Tanaka, Toshio
AU  - Tanaka T
AUID- ORCID: 0000-0002-0590-2893
AD  - Medical Affairs Bureau, Osaka Habikino Medical Center, Osaka 583-8588, Japan.
FAU - Inoue, Hitomi
AU  - Inoue H
AD  - Department of Immune Regulation, Immunology Frontier Research Center, Osaka 
      University, Suita, Osaka 565-0871, Japan.
FAU - Ono, Chikako
AU  - Ono C
AD  - Department of Molecular Virology, Research Institute for Microbial Diseases, 
      Osaka University, Suita, Osaka 565-0871, Japan.
FAU - Hashimoto, Shoji
AU  - Hashimoto S
AD  - Department of Clinical Laboratory, Osaka Habikino Medical Center, Osaka 583-8588, 
      Japan.
FAU - Kioi, Yoshiyuki
AU  - Kioi Y
AD  - Department of Immune Regulation, Immunology Frontier Research Center, Osaka 
      University, Suita, Osaka 565-0871, Japan.
FAU - Matsumoto, Hisatake
AU  - Matsumoto H
AUID- ORCID: 0000-0001-5771-570X
AD  - Department of Traumatology and Acute Critical Medicine, Osaka University Graduate 
      School of Medicine, Osaka University, Suita, Osaka 565-0871, Japan.
FAU - Matsuura, Hiroshi
AU  - Matsuura H
AUID- ORCID: 0000-0002-8618-0385
AD  - Department of Traumatology and Acute Critical Medicine, Osaka University Graduate 
      School of Medicine, Osaka University, Suita, Osaka 565-0871, Japan.
FAU - Matsubara, Tsunehiro
AU  - Matsubara T
AUID- ORCID: 0000-0002-0910-3124
AD  - Department of Traumatology and Acute Critical Medicine, Osaka University Graduate 
      School of Medicine, Osaka University, Suita, Osaka 565-0871, Japan.
FAU - Shimizu, Kentaro
AU  - Shimizu K
AD  - Department of Traumatology and Acute Critical Medicine, Osaka University Graduate 
      School of Medicine, Osaka University, Suita, Osaka 565-0871, Japan.
FAU - Ogura, Hiroshi
AU  - Ogura H
AD  - Department of Traumatology and Acute Critical Medicine, Osaka University Graduate 
      School of Medicine, Osaka University, Suita, Osaka 565-0871, Japan.
FAU - Matsuura, Yoshiharu
AU  - Matsuura Y
AUID- ORCID: 0000-0001-9091-8285
AD  - Department of Molecular Virology, Research Institute for Microbial Diseases, 
      Osaka University, Suita, Osaka 565-0871, Japan.
FAU - Kishimoto, Tadamitsu
AU  - Kishimoto T
AD  - Department of Immune Regulation, Immunology Frontier Research Center, Osaka 
      University, Suita, Osaka 565-0871, Japan; kishimoto@ifrec.osaka-u.ac.jp.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20200821
PL  - United States
TA  - Proc Natl Acad Sci U S A
JT  - Proceedings of the National Academy of Sciences of the United States of America
JID - 7505876
RN  - 0 (Antibodies, Monoclonal, Humanized)
RN  - 0 (Cytokines)
RN  - 0 (IL6 protein, human)
RN  - 0 (IL6R protein, human)
RN  - 0 (Interleukin-6)
RN  - 0 (Plasminogen Activator Inhibitor 1)
RN  - 0 (Receptors, Interleukin-6)
RN  - 0 (SERPINE1 protein, human)
RN  - I031V2H011 (tocilizumab)
SB  - IM
CIN - Proc Natl Acad Sci U S A. 2021 May 25;118(21):. PMID: 33972411
MH  - Adult
MH  - Aged
MH  - Antibodies, Monoclonal, Humanized/therapeutic use
MH  - Betacoronavirus
MH  - Burns/metabolism/pathology
MH  - COVID-19
MH  - Cells, Cultured
MH  - Coronavirus Infections/drug therapy/metabolism/pathology
MH  - Cytokine Release Syndrome/drug therapy/*metabolism/pathology
MH  - Cytokines/blood/metabolism
MH  - Endothelial Cells/drug effects/*metabolism
MH  - Female
MH  - Humans
MH  - Inflammation
MH  - Interleukin-6/blood/*metabolism
MH  - Male
MH  - Middle Aged
MH  - Pandemics
MH  - Plasminogen Activator Inhibitor 1/blood/*metabolism
MH  - Pneumonia, Viral/drug therapy/metabolism/pathology
MH  - Receptors, Interleukin-6/antagonists & inhibitors/metabolism
MH  - Respiratory Distress Syndrome/metabolism/pathology
MH  - SARS-CoV-2
MH  - Sepsis/metabolism/pathology
MH  - *Signal Transduction
PMC - PMC7486751
OTO - NOTNLM
OT  - COVID-19
OT  - IL-6
OT  - cytokine release syndrome
OT  - endothelial cell
OT  - tocilizumab
COIS- Competing interest statement: T.K. holds a patent for tocilizumab and receives 
      royalties from Actemra.
EDAT- 2020/08/23 06:00
MHDA- 2020/09/18 06:00
PMCR- 2020/08/21
CRDT- 2020/08/23 06:00
PHST- 2020/08/23 06:00 [pubmed]
PHST- 2020/09/18 06:00 [medline]
PHST- 2020/08/23 06:00 [entrez]
PHST- 2020/08/21 00:00 [pmc-release]
AID - 2010229117 [pii]
AID - 202010229 [pii]
AID - 10.1073/pnas.2010229117 [doi]
PST - ppublish
SO  - Proc Natl Acad Sci U S A. 2020 Sep 8;117(36):22351-22356. doi: 
      10.1073/pnas.2010229117. Epub 2020 Aug 21.