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Science 9 July 1999:
Vol. 285. no. 5425, pp. 248 - 251
DOI: 10.1126/science.285.5425.248
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HMG-1 as a Late Mediator of Endotoxin Lethality in Mice

Haichao Wang, 13* Ona Bloom, 3 Minghuang Zhang, 3 Jaideep M. Vishnubhakat, 3 Michael Ombrellino, 23 Jiantu Che, 3 Asia Frazier, 23 Huan Yang, 3 Svetlana Ivanova, 3 Lyudmila Borovikova, 3 Kirk R. Manogue, 3 Eugen Faist, 4 Edward Abraham, 5 Jan Andersson, 6 Ulf Andersson, 7 Patricia E. Molina, 2 Naji N. Abumrad, 2 Andrew Sama, 1 Kevin J. Tracey 23

Endotoxin, a constituent of Gram-negative bacteria, stimulates macrophages to release large quantities of tumor necrosis factor (TNF) and interleukin-1 (IL-1), which can precipitate tissue injury and lethal shock (endotoxemia). Antagonists of TNF and IL-1 have shown limited efficacy in clinical trials, possibly because these cytokines are early mediators in pathogenesis. Here a potential late mediator of lethality is identified and characterized in a mouse model. High mobility group-1 (HMG-1) protein was found to be released by cultured macrophages more than 8 hours after stimulation with endotoxin, TNF, or IL-1. Mice showed increased serum levels of HMG-1 from 8 to 32 hours after endotoxin exposure. Delayed administration of antibodies to HMG-1 attenuated endotoxin lethality in mice, and administration of HMG-1 itself was lethal. Septic patients who succumbed to infection had increased serum HMG-1 levels, suggesting that this protein warrants investigation as a therapeutic target.

1 Department of Emergency Medicine and
2 Department of Surgery, North Shore University Hospital-New York University School of Medicine, Manhasset, NY 11030, USA.
3 The Picower Institute for Medical Research, Manhasset, NY 11030, USA.
4 Department of Surgery, Klinicum Grosshadern, Ludwig-Maximilians University, Munich, Germany.
5 Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado Health Sciences Center, Denver, CO 80262, USA.
6 Department of Infectious Disease, Karolinska Institute, Huddinge University Hospital, Stockholm, Sweden.
7 Department of Rheumatology, Astrid Lindgren's Children's Hospital, Karolinska Institute, Stockholm, Sweden.
*   To whom correspondence should be addressed. E-mail: hwang{at}picower.edu

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A protein associated with Toll-like receptor (TLR) 4 (PRAT4A) is required for TLR-dependent immune responses.
K. Takahashi, T. Shibata, S. Akashi-Takamura, T. Kiyokawa, Y. Wakabayashi, N. Tanimura, T. Kobayashi, F. Matsumoto, R. Fukui, T. Kouro, et al. (2007)
J. Exp. Med. 204, 2963-2976
   Abstract »    Full Text »    PDF »
Multiple Effects of High Mobility Group Box Protein 1 in Skeletal Muscle Regeneration.
R. De Mori, S. Straino, A. Di Carlo, A. Mangoni, G. Pompilio, R. Palumbo, M. E. Bianchi, M. C. Capogrossi, and A. Germani (2007)
Arterioscler Thromb Vasc Biol 27, 2377-2383
   Abstract »    Full Text »    PDF »
Translocation of the novel cytokine HMGB1 to the cytoplasm and extracellular space coincides with the peak of clinical activity in experimentally UV-induced lesions of cutaneous lupus erythematosus.
V. Barkauskaite, M. Ek, K. Popovic, H.E. Harris, M. Wahren-Herlenius, and F. Nyberg (2007)
Lupus 16, 794-802
   Abstract »    PDF »
Tolerization with BLP down-regulates HMGB1 a critical mediator of sepsis-related lethality.
J. C. Coffey, J. H. Wang, R. Kelly, L. Romics Jr., A. O'Callaghan, C. Fiuza, and H. P. Redmond (2007)
J. Leukoc. Biol. 82, 906-914
   Abstract »    Full Text »    PDF »
Systemic inflammation and remote organ injury following trauma require HMGB1.
R. M. Levy, K. P. Mollen, J. M. Prince, D. J. Kaczorowski, R. Vallabhaneni, S. Liu, K. J. Tracey, M. T. Lotze, D. J. Hackam, M. P. Fink, et al. (2007)
Am J Physiol Regulatory Integrative Comp Physiol 293, R1538-R1544
   Abstract »    Full Text »    PDF »
A novel role for HMGB1 in TLR9-mediated inflammatory responses to CpG-DNA.
S. Ivanov, A.-M. Dragoi, X. Wang, C. Dallacosta, J. Louten, G. Musco, G. Sitia, G. S. Yap, Y. Wan, C. A. Biron, et al. (2007)
Blood 110, 1970-1981
   Abstract »    Full Text »    PDF »
Endogenous estrogen attenuates pulmonary artery vasoreactivity and acute hypoxic pulmonary vasoconstriction: the effects of sex and menstrual cycle.
T. Lahm, K. M. Patel, P. R. Crisostomo, T. A. Markel, M. Wang, C. Herring, and D. R. Meldrum (2007)
Am J Physiol Endocrinol Metab 293, E865-E871
   Abstract »    Full Text »    PDF »
Stage-Specific Secretion of HMGB1 in Cartilage Regulates Endochondral Ossification.
N. Taniguchi, K. Yoshida, T. Ito, M. Tsuda, Y. Mishima, T. Furumatsu, L. Ronfani, K. Abeyama, K.-i. Kawahara, S. Komiya, et al. (2007)
Mol. Cell. Biol. 27, 5650-5663
   Abstract »    Full Text »    PDF »
Receptor for advanced glycation end products (RAGE) in a dash to the rescue: inflammatory signals gone awry in the primal response to stress.
K. Herold, B. Moser, Y. Chen, S. Zeng, S. F. Yan, R. Ramasamy, J. Emond, R. Clynes, and A. M. Schmidt (2007)
J. Leukoc. Biol. 82, 204-212
   Abstract »    Full Text »    PDF »
The Anti-inflammatory Effects of Heat Shock Protein 72 Involve Inhibition of High-Mobility-Group Box 1 Release and Proinflammatory Function in Macrophages.
D. Tang, R. Kang, W. Xiao, H. Wang, S. K. Calderwood, and X. Xiao (2007)
J. Immunol. 179, 1236-1244
   Abstract »    Full Text »    PDF »
The Role of Nuclear Macromolecules in Innate Immunity.
D. S. Pisetsky (2007)
Proceedings of the ATS 4, 258-262
   Abstract »    Full Text »    PDF »
Chronic Sepsis Mortality Characterized by an Individualized Inflammatory Response.
M. F. Osuchowski, K. Welch, H. Yang, J. Siddiqui, and D. G. Remick (2007)
J. Immunol. 179, 623-630
   Abstract »    Full Text »    PDF »
Activation of Poly(ADP)-ribose Polymerase (PARP-1) Induces Release of the Pro-inflammatory Mediator HMGB1 from the Nucleus.
D. Ditsworth, W.-X. Zong, and C. B. Thompson (2007)
J. Biol. Chem. 282, 17845-17854
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Post-translational Methylation of High Mobility Group Box 1 (HMGB1) Causes Its Cytoplasmic Localization in Neutrophils.
I. Ito, J. Fukazawa, and M. Yoshida (2007)
J. Biol. Chem. 282, 16336-16344
   Abstract »    Full Text »    PDF »
Nuclear Heat Shock Protein 72 as a Negative Regulator of Oxidative Stress (Hydrogen Peroxide)-Induced HMGB1 Cytoplasmic Translocation and Release.
D. Tang, R. Kang, W. Xiao, L. Jiang, M. Liu, Y. Shi, K. Wang, H. Wang, and X. Xiao (2007)
J. Immunol. 178, 7376-7384
   Abstract »    Full Text »    PDF »
The Relationship between Apoptosis and High-Mobility Group Protein 1 Release from Murine Macrophages Stimulated with Lipopolysaccharide or Polyinosinic-Polycytidylic Acid.
W. Jiang, C. W. Bell, and D. S. Pisetsky (2007)
J. Immunol. 178, 6495-6503
   Abstract »    Full Text »    PDF »


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