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Chloroquine inhibits HMGB1 inflammatory signaling and protects mice from lethal sepsis.
- Source :
-
Biochemical pharmacology [Biochem Pharmacol] 2013 Aug 01; Vol. 86 (3), pp. 410-8. Date of Electronic Publication: 2013 May 22. - Publication Year :
- 2013
-
Abstract
- Sepsis is caused by an overwhelming immune response to bacterial infection. The discovery of high mobility group box 1 (HMGB1) as a late mediator of lethal sepsis has prompted investigation into the development of new therapeutics which specifically target this protein. Here, we show that chloroquine, an anti-malarial drug, prevents lethality in mice with established endotoxemia or sepsis. This effect is still observed even if administration of chloroquine is delayed. The protective effects of chloroquine were mediated through inhibition of HMGB1 release in macrophages, monocytes, and endothelial cells, thereby preventing its cytokine-like activities. As an inhibitor of autophagy, chloroquine specifically inhibited HMGB1-induced Iκ-B degradation and NF-κB activation. These findings define a novel mechanism for the anti-inflammatory effects of chloroquine and also suggest a new potential clinical use for this drug in the setting of sepsis.<br /> (Crown Copyright © 2013. Published by Elsevier Inc. All rights reserved.)
- Subjects :
- Animals
Cell Line
HMGB1 Protein metabolism
Macrophages drug effects
Macrophages metabolism
Macrophages pathology
Male
Mice
Mice, Inbred BALB C
Sepsis metabolism
Sepsis mortality
Signal Transduction physiology
Survival Rate
Antimalarials therapeutic use
Chloroquine therapeutic use
HMGB1 Protein antagonists & inhibitors
Inflammation Mediators therapeutic use
Sepsis prevention & control
Signal Transduction drug effects
Subjects
Details
- Language :
- English
- ISSN :
- 1873-2968
- Volume :
- 86
- Issue :
- 3
- Database :
- MEDLINE
- Journal :
- Biochemical pharmacology
- Publication Type :
- Academic Journal
- Accession number :
- 23707973
- Full Text :
- https://doi.org/10.1016/j.bcp.2013.05.013