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IL-6 trans-signaling induces plasminogen activator inhibitor-1 from vascular endothelial cells in cytokine release syndrome.
Proc Natl Acad Sci U S A. 2020 09 08; 117(36):22351-22356.PN

Abstract

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.

Authors+Show Affiliations

Department of Immune Regulation, Immunology Frontier Research Center, Osaka University, Suita, Osaka 565-0871, Japan.Medical Affairs Bureau, Osaka Habikino Medical Center, Osaka 583-8588, Japan.Department of Immune Regulation, Immunology Frontier Research Center, Osaka University, Suita, Osaka 565-0871, Japan.Department of Molecular Virology, Research Institute for Microbial Diseases, Osaka University, Suita, Osaka 565-0871, Japan.Department of Clinical Laboratory, Osaka Habikino Medical Center, Osaka 583-8588, Japan.Department of Immune Regulation, Immunology Frontier Research Center, Osaka University, Suita, Osaka 565-0871, Japan.Department of Traumatology and Acute Critical Medicine, Osaka University Graduate School of Medicine, Osaka University, Suita, Osaka 565-0871, Japan.Department of Traumatology and Acute Critical Medicine, Osaka University Graduate School of Medicine, Osaka University, Suita, Osaka 565-0871, Japan.Department of Traumatology and Acute Critical Medicine, Osaka University Graduate School of Medicine, Osaka University, Suita, Osaka 565-0871, Japan.Department of Traumatology and Acute Critical Medicine, Osaka University Graduate School of Medicine, Osaka University, Suita, Osaka 565-0871, Japan.Department of Traumatology and Acute Critical Medicine, Osaka University Graduate School of Medicine, Osaka University, Suita, Osaka 565-0871, Japan.Department of Molecular Virology, Research Institute for Microbial Diseases, Osaka University, Suita, Osaka 565-0871, Japan.Department of Immune Regulation, Immunology Frontier Research Center, Osaka University, Suita, Osaka 565-0871, Japan; kishimoto@ifrec.osaka-u.ac.jp.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

32826331

Citation

Kang, Sujin, et al. "IL-6 Trans-signaling Induces Plasminogen Activator Inhibitor-1 From Vascular Endothelial Cells in Cytokine Release Syndrome." Proceedings of the National Academy of Sciences of the United States of America, vol. 117, no. 36, 2020, pp. 22351-22356.
Kang S, Tanaka T, Inoue H, et al. IL-6 trans-signaling induces plasminogen activator inhibitor-1 from vascular endothelial cells in cytokine release syndrome. Proc Natl Acad Sci U S A. 2020;117(36):22351-22356.
Kang, S., Tanaka, T., Inoue, H., Ono, C., Hashimoto, S., Kioi, Y., Matsumoto, H., Matsuura, H., Matsubara, T., Shimizu, K., Ogura, H., Matsuura, Y., & Kishimoto, T. (2020). IL-6 trans-signaling induces plasminogen activator inhibitor-1 from vascular endothelial cells in cytokine release syndrome. Proceedings of the National Academy of Sciences of the United States of America, 117(36), 22351-22356. https://doi.org/10.1073/pnas.2010229117
Kang S, et al. IL-6 Trans-signaling Induces Plasminogen Activator Inhibitor-1 From Vascular Endothelial Cells in Cytokine Release Syndrome. Proc Natl Acad Sci U S A. 2020 09 8;117(36):22351-22356. PubMed PMID: 32826331.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - IL-6 trans-signaling induces plasminogen activator inhibitor-1 from vascular endothelial cells in cytokine release syndrome. AU - Kang,Sujin, AU - Tanaka,Toshio, AU - Inoue,Hitomi, AU - Ono,Chikako, AU - Hashimoto,Shoji, AU - Kioi,Yoshiyuki, AU - Matsumoto,Hisatake, AU - Matsuura,Hiroshi, AU - Matsubara,Tsunehiro, AU - Shimizu,Kentaro, AU - Ogura,Hiroshi, AU - Matsuura,Yoshiharu, AU - Kishimoto,Tadamitsu, Y1 - 2020/08/21/ PY - 2020/8/23/pubmed PY - 2020/9/18/medline PY - 2020/8/23/entrez KW - COVID-19 KW - IL-6 KW - cytokine release syndrome KW - endothelial cell KW - tocilizumab SP - 22351 EP - 22356 JF - Proceedings of the National Academy of Sciences of the United States of America JO - Proc Natl Acad Sci U S A VL - 117 IS - 36 N2 - 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. SN - 1091-6490 UR - https://www.unboundmedicine.com/medline/citation/32826331/IL_6_trans_signaling_induces_plasminogen_activator_inhibitor_1_from_vascular_endothelial_cells_in_cytokine_release_syndrome_ L2 - http://www.pnas.org/cgi/pmidlookup?view=long&pmid=32826331 DB - PRIME DP - Unbound Medicine ER -