Table of Contents Author Guidelines Submit a Manuscript
Evidence-Based Complementary and Alternative Medicine
Volume 2013, Article ID 716481, 14 pages
http://dx.doi.org/10.1155/2013/716481
Research Article

ATF3 Protects against LPS-Induced Inflammation in Mice via Inhibiting HMGB1 Expression

1PhD Program in Pharmacology and Toxicology, Tzu-Chi University, No. 701, Chung Yang Road, Section 3, Hualien 97004, Taiwan
2Department of Emergency Medicine, Buddhist Tzu Chi General Hospital, No. 707, Section 3, Chung Yang Road, Hualien 97004, Taiwan
3Department of Medical Research, Buddhist Tzu Chi General Hospital and Department of Pediatrics, Tzu Chi University, No. 707, Section 3, Chung Yang Road, Hualien 97004, Taiwan
4Department of Physiology, School of Medicine, College of Medicine, Taipei Medical University, 250 Wu-Hsing Street, Taipei City 110, Taiwan
5Institutes of Medical Sciences, College of Medicine, Tzu-Chi University, No. 701, Chung Yang Road, Section 3, Hualien 97004, Taiwan
6Center of Vascular Medicine, College of Life Sciences, Tzu-Chi University, No. 701, Chung Yang Road, Section 3, Hualien 97004, Taiwan
7Division of Nephrology, Department of Internal Medicine, Taipei Medical University Hospital, No. 252, Wu Hsing Street, Taipei City 110, Taiwan
8Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, 250 Wu-Hsing Street, Taipei City 110, Taiwan
9Department of pharmacology, Tzu-Chi University, No. 701, Chung Yang Road, Section 3, Hualien 97004, Taiwan

Received 15 April 2013; Accepted 6 June 2013

Academic Editor: Y. Ohta

Copyright © 2013 Pei-Fang Lai et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Lipopolysaccharide (LPS) triggers innate immunity mainly via TLR4 signaling. ATF3 is a negative regulator of TLR4 signaling. HMGB1 plays a critical role in the final step of sepsis. However, the mechanisms of ATF3 and the role of HMGB1 in regulating innate immunity-induced sepsis are incompletely understood. In this study, we found that serum HMGB1 levels were 10-fold higher in patients with sepsis than normal controls. We further demonstrated that ATF3 gene knockout in mice subjected to LPS-induced endotoxemia correlates with an increase in the mortality rate and the elevated expression of IL-6, TNF-α, NO, MCP-1, and HMGB1 in the lung tissues or serum. The biochemical effects of ATF3 were observed in in vitro macrophages and blocked by ATF3 siRNA treatment. We have also shown that adeno-associated virus-mediated ATF3 gene transfer protected ATF3 knockout mice from LPS-induced mortality. In addition, ATF3 knockdown increased LPS-induced release of HMGB1. In conclusion, upregulation of ATF3 contributes to the reduced release of inflammatory molecules, especially HMGB1, which induced lung injury and increased the survival rate of mice after LPS challenge. Therefore, suppressing LPS-induced inflammation with ATF3 induction or ATF3 mimetics may be an important strategy for sepsis therapy.