High-mobility group box-1 protein induce inflammatory response after pulmonary injury



High-mobility group box 1 (HMGB1), a highly conserved non-histone chromosomal protein, was found to act as a potent proinflammatory cytokine and a mediator that participated in the development of systemic inflammatory response. Forty wild type C57BL/6 male (25-30gms) mice were randomly divided into three groups: saline control group; anti-HMGB1 antibody treated group and untreated group. Each group received intratracheal instillation twice per week for 4 consecutive months. 24 hours after the last exposure, anaesthetize the mice with chloral hydrate, bronchoalveolar lavage fluid was collected for cytokines analysis were measured by enzyme linked immunosorbent assay (ELISA). The level of the HMGB1 in lung tissue was determined by real-time PCR and western blot. Lung were fixed with 4% paraformaldehyde for histopathological detection. The serum level of HMGB1 increased after lung injury [peaked 2-5 hr] after lung injury, furthermore this upregulation in HMGB1 associated with increased proinflammatory cytokines [TNF-α, IL-6, IL-1β]. The injection of anti-HMGB1 antibody suppressed inflammatory reaction and improved the survival rate compared with control mice [71.3% vs. 29.4% P=0.031]

Keywords:  HMGB1; TNF-α; IL-6; IL-1β; Survival rate

Copyright © 2015 by The American Society for BioMedicine and BM-Publisher, Inc.

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  1. 1. Huang W, Tang Y, Li L. HMGB1, a potent proinflammatory cytokine in sepsis. Cytokine 2010;51 (2) 119–126. [PubMed]2. Huang LF, Yao YM, Dong N, Yu Y, He LX, et al. Association of high mobility group box-1 protein levels with sepsis and outcome of severely burned patients. Cytokine 2011;53 (1) 29–34.[PubMed]

    3. Park JS, Svetkauskaite D, He Q, Kim JY, Strassheim D, et al. Involvement of toll-like receptors 2 and 4 in cellular activation by high mobility group box 1 protein. J Biol Chem 2004; 279(9) 7370–7377. [PubMed]

    4. Mogensen TH. Pathogen recognition and inflammatory signaling in innate immune defenses. Clin Microbiol Rev 2009; 22(2) 240–273. [PubMed]

    5. Ware LB, Matthay MA. The acute respiratory distress syndrome. N Engl J Med 2000; 342: 1334–1349. [PubMed]

    6. Miller BE, Levy JH. The inflammatory response to cardiopulmonary bypass. J Cardiothorac Vasc Anesth 1997;11: 355–366. [PubMed]

    7. Gribar SC, Richardson WM, Sodhi CP, Hackam DJ . No longer an innocent bystander: epithelial toll-like receptor signaling in the development of mucosal inflammation. Mol Med 2008;14: 645–659. [PubMed]

    8. Patel U, Clemence G, Latruffe C, Reddy P, Chu Q, Heyman C, Griffin A. Role of peroxisome proliferator activator receptor-gamma (PPAR-γ) in lung sepsis. American journal of BioMedicine 2014;2(3):270–291. [Abstract/Full-Text]

    9. Li J, Wang H, Mason JM, Levine J, Yu M, et al. Recombinant HMGB1 with cytokine-stimulating activity. J Immunol Methods 2004; 289: 211–223. [PubMed]

    10. Yun Y, Zheng X, Chen L, Su Y, Kim C, Zhao M. Expression of ATF3 in mouse protects the liver against sepsis via inhibiting HMGB expression. American journal of BioMedicine 2014; 2(3):337–349. [Abstract/Full-Text]

    11. Yang H, Wang H, Czura CJ, Tracey KJ. The cytokine activity of HMGB1. J Leukoc Biol 2005;78: 1–8. [PubMed]

    12. Degryse B, Bonaldi T, Scaffidi P, Muller S, Resnati M, et al.The high mobility group (HMG) boxes of the nuclear protein HMG1 induce chemotaxis and cytoskeleton reorganization in rat smooth muscle cells. J Cell Biol 2001; 152: 1197–1206. [PubMed]

    13. Ueno H, Matsuda T, Hashimoto S, Amaya F, Kitamura Y, et al. (2004) Contributions of high mobility group box protein in experimental and clinical acute lung injury. Am J Respir Crit Care Med 170: 1310–1316. [PubMed]

    14. Park WY, Goodman RB, Steinberg KP, Ruzinski JT, Radella F, 2nd, et al. Cytokine balance in the lungs of patients with acute respiratory distress syndrome. Am J Respir Crit Care Med 2001;164: 1896–1903. [PubMed]

    15. Baudouin S. Innate immune defense on the attack in acute lung injury. Crit Care Med 2010;38: 328–329. [PubMed]

    16. Park JS, Gamboni-Robertson F, He Q, Svetkauskaite D, Kim JY, et al. High mobility group box 1 protein interacts with multiple Toll-like receptors. Am J Physiol Cell Physiol 2006; 290: C917–924. [PubMed]

    17. Abraham E, Arcaroli J, Carmody A, Wang H, and Tracey KJ. HMG-1 as a mediator of acute lung inflammation. J Immunol 2000;165: 2950–2954. [Abstract/FREE Full Text]

    18. Boonyaratanakornkit V, Melvin V, Prendergast P, Altmann M, Ronfani L, Bianchi ME, Taraseviciene L, et al. High-mobility group chromatin proteins 1 and 2 functionally interact with steroid hormone receptors to enhance their DNA binding in vitro and transcriptional activity in mammalian cells. Mol Cell Biol 1998;18: 4471–4487. [Abstract/FREE Full Text]

    19. Fiuza C, Bustin M, Talwar S, Tropea M, Gerstenberger E, Shelhamer JH, and Suffredini AF. Inflammation-promoting activity of HMGB1 on human microvascular endothelial cells. Blood 2003;101: 2652–2660. [Abstract/FREE Full Text]

    20. Jayaraman L, Moorthy NC, Murthy KG, Manley JL, Bustin M, and Prives C. High mobility group protein-1 (HMG-1) is a unique activator of p53. Genes Dev 1998;12: 462–472. [Abstract/FREE Full Text]

    21. Biscetti F, Straface G, De Cristofaro R, Lancellotti S, Rizzo P, et al. High-mobility group box-1 protein promotes angiogenesis after peripheral ischemia in diabetic mice through a VEGF-dependent mechanism. Diabetes 2010;59: 1496–1505. [PubMed]

    22. Nahorski R, Ploeger A, Ludovici L, Marchis R, Eikan S, Maria M, Gille F; Mazzon D. Astragaloside attenuates cardiotoxicity effects of Doxorubicin by inhibiting TLR4/NF-кB signaling pathway. American journal of BioMedicine 2014; 2(4):463–479. [Abstract/FREE Full Text]

    23. Ulloa L, Messmer D. High-mobility group box 1 (HMGB1) protein: friend and foe. Cytokine Growth Factor Rev 2006;17: 189–201. [PubMed]

    24. Stros M. HMGB proteins: interactions with DNA and chromatin. Biochim Biophys Acta 2010;1799: 101–113. [PubMed]

    25. Nasser Ghaly Yousif. Fibronectin promotes migration and invasion of ovarian cancer cells through up‐regulation of FAK–PI3K/Akt pathway. Cell biology international 2014; 38:85-91. [Abstract/FREE Full Text]

    26. Yanai H, Ban T, Taniguchi T. High-mobility group box family of proteins: ligand and sensor for innate immunity. Trends Immunol  2012; 3: 633–640. [PubMed]

    27. Popovic PJ, DeMarco R, Lotze MT, Winikoff SE, Bartlett DL, et al. High mobility group B1 protein suppresses the human plasmacytoid dendritic cell response to TLR9 agonists. J Immunol 2006;177: 8701–8707. [PubMed]

    28. Austin EW, Yousif NG, Ao L, Cleveland JC, Fullerton DA, Meng X. Ghrelin reduces myocardial injury following global ischemia and reperfusion via suppression of myocardial inflammatory response. American Journal of BioMedicine 2013; 1(2): 38–48. [Abstract/FREE Full Text]

    29. Dumitriu IE, Baruah P, Bianchi ME, Manfredi AA, Rovere-Querini P. Requirement of HMGB1 and RAGE for the maturation of human plasmacytoid dendritic cells. Eur J Immunol. 2005 ;35(7):2184-90. [PubMed]

    30. Popovic PJ, DeMarco R, Lotze MT, Winikoff SE, Bartlett DL, Krieg AM, Guo ZS, et al.

    High mobility group B1 protein suppresses the human plasmacytoid dendritic cell response to TLR9 agonists. J Immunol. 2006;177(12):8701-7. [PubMed]

    31. Bianchi ME, Manfredi AA. High-mobility group box 1 (HMGB1) protein at the crossroads between innate and adaptive immunity. Immunol Rev. 2007;220:35-46. [PubMed]

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Research Article
DOI: http://dx.doi.org/10.18081/2333-5106/015-3/495-514
American Journal of BioMedicine 2015, Volume 3, Issue 3, pages 195-214
Received April 03, 2015; accepted June; 30, 2015, Published August 05, 2015

How to cite this article
Golemis JH, Rudensky LJ, Moltedo TK. High-mobility group box-1 protein induce inflammatory response after pulmonary injury. American Journal of BioMedicine 2015;3(3):195-214
Research Article
1. Abstract
2. Keywords
3. Introduction
5. Results
6. Discussion
7. References

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