Interferons prime endothelium for toll-like receptor-mediated thrombin generation.
cytokine release syndrome
endothelium
interferons
tissue factor
toll-like receptors
Journal
Journal of thrombosis and haemostasis : JTH
ISSN: 1538-7836
Titre abrégé: J Thromb Haemost
Pays: England
ID NLM: 101170508
Informations de publication
Date de publication:
28 Dec 2023
28 Dec 2023
Historique:
received:
30
08
2023
revised:
14
12
2023
accepted:
16
12
2023
medline:
2
1
2024
pubmed:
2
1
2024
entrez:
30
12
2023
Statut:
aheadofprint
Résumé
Respiratory infection is associated with microvascular thrombus formation and marked elevation of cytokines. The role of cytokines elaborated by pulmonary epithelium in thrombotic responses is poorly understood. Our goal was to identify cytokines of pulmonary epithelial cell origin that enhance thrombin generation in endothelium at concentrations equal to or less than those found in the circulation during infection. We screened multiple cytokines produced by pulmonary epithelium for the ability to enhance toll-like receptor (TLR)-mediated endothelial thrombin generation. Effects of cytokines on tissue factor and thrombomodulin expression, cytokine selectivity for different TLRs, and prothrombotic activity of endogenous cytokines in conditioned medium from pulmonary human epithelial cells were evaluated. MIP-1β, MCP-1, IL-10, IL-6, IL-1β, TNFα, IFNα, IFNβ, and IFNγ were tested for their ability to enhance TLR3-mediated thrombin generation on endothelial cells. Only IFNs and TNFα promoted TLR3-mediated thrombin generation at levels that circulate during infection. IFNs robustly enhanced tissue factor expression when used in conjunction with TLR agonists and reduced thrombomodulin expression in endothelium independently of TLRs. IFNα, which is typically elevated with viral infection, only synergized with TLR3 agonists mimicking viral PAMPs. In contrast, IFNγ, which is typically in bacterial infection, synergized more effectively with TLR4 agonists released by bacteria. Conditioned media from inflamed pulmonary epithelial cells primed endothelium for TLR-mediated thrombin generation. Anti-IFN type I antibodies blocked this effect, indicating that endogenous IFNs prime endothelium for TLR-mediated thrombin generation. IFNs elaborated by pulmonary epithelium are necessary and sufficient to enhance TLR-mediated thrombin generation.
Sections du résumé
BACKGROUND
BACKGROUND
Respiratory infection is associated with microvascular thrombus formation and marked elevation of cytokines. The role of cytokines elaborated by pulmonary epithelium in thrombotic responses is poorly understood.
AIMS
OBJECTIVE
Our goal was to identify cytokines of pulmonary epithelial cell origin that enhance thrombin generation in endothelium at concentrations equal to or less than those found in the circulation during infection.
METHODS
METHODS
We screened multiple cytokines produced by pulmonary epithelium for the ability to enhance toll-like receptor (TLR)-mediated endothelial thrombin generation. Effects of cytokines on tissue factor and thrombomodulin expression, cytokine selectivity for different TLRs, and prothrombotic activity of endogenous cytokines in conditioned medium from pulmonary human epithelial cells were evaluated.
RESULTS
RESULTS
MIP-1β, MCP-1, IL-10, IL-6, IL-1β, TNFα, IFNα, IFNβ, and IFNγ were tested for their ability to enhance TLR3-mediated thrombin generation on endothelial cells. Only IFNs and TNFα promoted TLR3-mediated thrombin generation at levels that circulate during infection. IFNs robustly enhanced tissue factor expression when used in conjunction with TLR agonists and reduced thrombomodulin expression in endothelium independently of TLRs. IFNα, which is typically elevated with viral infection, only synergized with TLR3 agonists mimicking viral PAMPs. In contrast, IFNγ, which is typically in bacterial infection, synergized more effectively with TLR4 agonists released by bacteria. Conditioned media from inflamed pulmonary epithelial cells primed endothelium for TLR-mediated thrombin generation. Anti-IFN type I antibodies blocked this effect, indicating that endogenous IFNs prime endothelium for TLR-mediated thrombin generation.
CONCLUSION
CONCLUSIONS
IFNs elaborated by pulmonary epithelium are necessary and sufficient to enhance TLR-mediated thrombin generation.
Identifiants
pubmed: 38159649
pii: S1538-7836(23)00923-6
doi: 10.1016/j.jtha.2023.12.021
pii:
doi:
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Informations de copyright
Copyright © 2023 International Society on Thrombosis and Haemostasis. Published by Elsevier Inc. All rights reserved.