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* Laboratory of Shock, Department of Pathophysiology, Xiangya School of Medicine, Changsha, People’s Republic of China;
Department of Pediatrics, Xiangya Hospital, Central South University, Changsha, People’s Republic of China;
College of Optometry, University of Houston, Houston, TX 77204;
Department of Emergency Medicine, North Shore University Hospital, New York University School of Medicine, Manhasset, NY 11030;
¶ Feinstein Institute for Medical Research, Manhasset, NY 11030; and
|| Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215
High-mobility-group box 1 (HMGB1), a nuclear protein, has recently been identified as an important mediator of local and systemic inflammatory diseases when released into the extracellular milieu. Anti-inflammatory regulation by the stress response is an effective autoprotective mechanism when the host encounters harmful stimuli, but the mechanism of action remains incompletely delineated. In this study, we demonstrate that increases in levels of a major stress-inducible protein, heat shock protein 72 (Hsp72) by gene transfection attenuated LPS- or TNF-
-induced HMGB1 cytoplasmic translocation and release. The mechanisms involved inhibition of the chromosome region maintenance 1 (CRM1)-dependent nuclear export pathway. Overexpression of Hsp72 inhibited CRM1 translocation and interaction between HMGB1 and CRM1 in macrophages post-LPS and TNF- treatment. In addition, overexpression of Hsp72 strongly inhibited HMGB1-induced cytokine (TNF-, IL-1
) expression and release, which correlated closely with: 1) inhibition of the MAP kinases (p38, JNK, and ERK); and 2) inhibition of the NF-
B pathway. Taken together, these experiments suggest that the anti-inflammatory activity of Hsp72 is achieved by interfering with both the release and proinflammatory function of HMGB1. Our experimental data provide important insights into the anti-inflammatory mechanisms of heat shock protein protection.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by Grants 30500485 (to D.T.) and 30330280 (to X.X.) from the National Natural Sciences Foundation of China, the Major National Basic Research Program of China Grant G2000056908 (to X.X.), the Specialized Research Fund for the Doctoral Program of Higher Education of China Grant 20060533009 (to X.X.), and the Innovative Program of Central South University for Post-graduate Research Grant 2005-75239 (to D.T.), and in part by National Institute of General Medical Sciences Grants R01GM063075 and R01GM070817 (to H.W.) from the National Institutes of Health.
2 D.T. and R.K. contributed equally to this paper.
3 Address correspondence and reprint requests to Dr. Xianzhong Xiao, Department of Pathophysiology, Xiangya School of Medicine, Central South University, 110 Xiangya Road, Changsha, Hunan 410008, People’s Republic of China. E-mail address: xianzhongxiao{at}xysm.net or Dr. Haichao Wang, Department of Emergency Medicine, North Shore University Hospital-NYU School of Medicine, 350 Community Drive, NY 11030. E-mail address: hwang{at}nshs.edu
4 Abbreviations used in this paper: HMGB1, high-mobility group box 1; CRM1, chromosome region maintenance 1; HS, heat shock; HSR, heat shock response; HSP, heat shock protein; Hsp72, heat shock protein 72; Hsp73, heat shock protein 73.
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  J. R. Klune, T. R. Billiar, and A. Tsung HMGB1 preconditioning: therapeutic application for a danger signal? J. Leukoc. Biol., March 1, 2008; 83(3): 558 - 563. [Abstract] [Full Text] [PDF]
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