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Proinflammatory Function in Macrophages High-Mobility-Group The Anti-inflammatory Effects of Heat Shock Protein 72 Involve Inhibition of High-Mobility-Group Box 1 Release and Proinflammatory Function in Macrophages This information is current as of September 25, 2021. Daolin Tang, Rui Kang, Weimin Xiao, Haichao Wang, Stuart K. Calderwood and Xianzhong Xiao J Immunol 2007; 179:1236-1244; ; doi: 10.4049/jimmunol.179.2.1236 http://www.jimmunol.org/content/179/2/1236 Downloaded from References This article cites 62 articles, 26 of which you can access for free at: http://www.jimmunol.org/content/179/2/1236.full#ref-list-1 http://www.jimmunol.org/ Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication by guest on September 25, 2021 *average Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2007 by The American Association of Immunologists All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology The Anti-Inflammatory Effects of Heat Shock Protein 72 Involve Inhibition of High-Mobility-Group Box 1 Release and Proinflammatory Function in Macrophages1 Daolin Tang,2* Rui Kang,2† Weimin Xiao,*‡ Haichao Wang,3§¶ Stuart K. Calderwood,ʈ and Xianzhong Xiao3* 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 incom- pletely 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 Downloaded from 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-␣ treat- ment. 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 http://www.jimmunol.org/ mechanisms of heat shock protein protection. The Journal of Immunology, 2007, 179: 1236–1244. epsis is a systemic inflammatory syndrome that can lead flammatory cytokine that mediates the response to infection, in- to lethal organ damage. Despite advances in antibiotic jury, and inflammation (4–8). Although residing predominantly in S therapy and intensive care, the overall mortality from the nucleus of quiescent macophages/monocytes, HMGB1 can be severe sepsis exceeds 30% in the United States (1). Initiated by actively secreted in response to exogenous and endogenous in- an infection, the pathogenesis of sepsis is attributable, at least in flammatory stimuli such as endotoxin, TNF-␣, IL-1, IFN-␥, and part, to dysregulated systemic inflammatory responses charac- hydrogen peroxide (4, 9–11). In addition, HMGB1 can be pas- terized by excessive accumulation of various proinflammatory sively released by necrotic cells (6). HMGB1 has a chromosome by guest on September 25, 2021 cytokines (2, 3). region maintenance 1 (CRM1)-dependent nuclear active export Recent evidence indicates that high-mobility-group box 1 pathway (12). Once released from cells, HMGB1 can bind to cell (HMGB1),4 a ubiquitous nuclear protein, is an important proin- surface receptors including the receptor for advanced glycation end products), TLR-2, and TLR-4 and mediate cellular responses including chemotactic cell movement and release of proinflamma- *Laboratory of Shock, Department of Pathophysiology, Xiangya School of Medicine, Changsha, People’s Republic of China; †Department of Pediatrics, Xiangya Hospital, tory cytokines (e.g., TNF-␣ and IL-1; Refs. 13–17). Anti-HMGB1 Central South University, Changsha, People’s Republic of China; ‡College of Op- Abs or specific antagonists protect mice from lethal endotoxemia tometry, University of Houston, Houston, TX 77204; §Department of Emergency Medicine, North Shore University Hospital, New York University School of Medi- or sepsis, even when the first dose are given 24 h after onset of cine, Manhasset, NY 11030; ¶Feinstein Institute for Medical Research, Manhasset, diseases (4, 18), establishing HMGB1 as an important therapeutic ʈ NY 11030; and Beth Israel Deaconess Medical Center, Harvard Medical School, target for inflammatory diseases (5, 19). Boston, MA 02215 MAPKs and the NF-␬B/I␬B pathway play essential roles in in- Received for publication April 5, 2007. Accepted for publication April 24, 2007. flammation because of the rapidity of activation and potency in The costs of publication of this article were defrayed in part by the payment of page activation of transcription of NF-␬B (20, 21). The MAPK family charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. mainly includes ERK, p38 kinase, and JNK. Once activated, the 1 This work was supported by Grants 30500485 (to D.T.) and 30330280 (to X.X.) MAPKs modulate the functional responses of cells through from the National Natural Sciences Foundation of China, the Major National Basic phosphorylation of transcription factors and activation of other Research Program of China Grant G2000056908 (to X.X.), the Specialized Research kinases. NF-␬B regulates the transcription of many genes in- 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 volved in immunity, inflammation, and protection from pro- Research Grant 2005-75239 (to D.T.), and in part by National Institute of General grammed cell death (22). Medical Sciences Grants R01GM063075 and R01GM070817 (to H.W.) from the National Institutes of Health. The heat shock (HS) response (HSR) is a universal stress re- sponse activated in all prokaryotes and eukaryotes and is repre- 2 D.T. and R.K. contributed equally to this paper. sented at the molecular level by the induction of heat shock protein 3 Address correspondence and reprint requests to Dr. Xianzhong Xiao, Department of Pathophysiology, Xiangya School of Medicine, Central South University, 110 (HSP) synthesis (23). The Hsp70 family is the best characterized Xiangya Road, Changsha, Hunan 410008, People’s Republic of China. E-mail ad- dress: [email protected] or Dr. Haichao Wang, Department of Emergency Medicine, North Shore University Hospital-NYU School of Medicine, 350 Commu- HSP, heat shock protein; Hsp72, heat shock protein 72; Hsp73, heat shock pro- nity Drive, NY 11030. E-mail address: [email protected] tein 73. 4 Abbreviations used in this paper: HMGB1, high-mobility group box 1; CRM1, chromosome region maintenance 1; HS, heat shock; HSR, heat shock response; Copyright © 2007 by The American Association of Immunologists, Inc. 0022-1767/07/$2.00 www.jimmunol.org The Journal of Immunology 1237 of these and include the constitutive Hsp73, and stress-inducible peroxidase-conjugated secondary Abs for1hat25°C, the signals were Hsp72. The HSPs are involved in protecting the organism from a visualized by diaminobenzidine detection (Boster Biotech) according to the variety of insults including ischemia/reperfusion and oxidative in- manufacturer’s instruction. jury (24, 25). Although the underlying mechanism of this protec- Immunocytochemical analysis tion involves their chaperone functions (e.g., preventing abnormal Cells were cultured on glass coverslips and fixed in 4% formaldehyde for protein folding or aggregation; Ref. 26), recent work also shows 30 min at room temperature before detergent extraction with 0.1% Triton that HSPs directly interferes with cell death pathways including X-100 for 10 min at 4°C. Coverslips were saturated with PBS containing apoptosis and necrosis (27, 28). Induction of Hsp72 in vitro by 2%BSAfor1hatroom temperature and processed for immunofluores- heat shock or Hsp72 overexpression can reduce mortality in cence with anti-HMGB1 or anti-CRM1 Ab (BD Biosciences) followed by experimental models of septic shock, endotoxemia, and adult Cy3 (Sigma-Aldrich)- or FITC (Boster Biotech)-conjugated Ig, respec- tively. Nuclear morphology was analyzed with the fluorescent dye Hoechst respiratory distress syndrome, and can regulate expression of 33258 (Sigma-Aldrich). Between all incubation steps, cells were inflammatory genes, such as TNF-␣, IL-1, IL-12, IL-10, and washed three times for 3 min with PBS containing 0.2% BSA. Images IL-18 (29–36). were taken with a fluorescence
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