Journal
BIOCHEMICAL PHARMACOLOGY
Volume 86, Issue 3, Pages 410-418Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bcp.2013.05.013
Keywords
HMGB1; Chloroquine; Sepsis; Autophagy; NF-kappa B; Beclin 1
Categories
Funding
- National Natural Sciences Foundation of China [30973234, 31171328, 81270616, 81100359]
- National Institutes of Health [R01CA160417]
- NATIONAL CANCER INSTITUTE [R01CA160417] Funding Source: NIH RePORTER
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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 1 kappa-B degradation and NF-kappa B 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. Crown Copyright (C) 2013 Published by Elsevier Inc. All rights reserved.
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