* Department of Medicine, Rheumatology Research Unit, Karolinska Hospital, Stockholm, Sweden;
Department of Woman and Child Health, Karolinska Institutet, Astrid Lindgren Children’s Hospital, Stockholm, Sweden; and
Laboratory of Biomedical Science, North Shore–Long Island Jewish Research Institute, Manhasset, New York
Correspondence: Professor Ulf Andersson, Department of Rheumatology, Astrid Lindgren Children’s Hospital, Q1:02,171 76, Stockholm, Sweden. E-mail: ulf{at}mbox313.swipnet.se
HMGB1 (high mobility group box chromosomal protein 1), historically known as an abundant, nonhistone architectural chromosomal protein, is extremely conserved across species. As a nuclear protein, HMGB1 stabilizes nucleosomes and allows bending of DNA that facilitates gene transcription. Unexpectedly, recent studies identified extracellular HMGB1 as a potent macrophage-activating factor, signaling via the receptor for advanced glycation end-products to induce inflammatory responses. It is released as a late mediator during inflammation and participates in the pathogenesis of systemic inflammation after the early mediator response has resolved. HMGB1 occupies a critical role as a proinflammatory mediator passively released by necrotic but not apoptotic cells. Necrotic Hmgb1-/- cells mediate minimal inflammatory responses. Stimulated macrophages actively secrete HMGB1 to promote inflammation and in turn, stimulate production of multiple, proinflammatory cytokines. HMGB1 mediates endotoxin lethality, acute lung injury, arthritis induction, activation of macrophages, smooth muscle cell chemotaxis, and epithelial cell barrier dysfunction. HMGB1 is structurally composed of three different domains: two homologous DNA-binding sequences entitled box A and box B and a highly, negatively charged C terminus. The B box domain contains the proinflammatory cytokine functionality of the molecule, whereas the A box region has an antagonistic, anti-inflammatory effect with therapeutic potential. Administration of highly purified, recombinant A box protein or neutralizing antibodies against HMGB1 rescued mice from lethal sepsis, even when initial treatment was delayed for 24 h after the onset of infection, establishing a clinically relevant therapeutic window that is significantly wider than for other known cytokines.
Key Words: inflammation • nuclear cytokine • necrosis • RAGE ligand • sepsis • arthritis
This article has been cited by other articles:
 |
|
 |
|
  N. Hamada, T. Maeyama, T. Kawaguchi, M. Yoshimi, J. Fukumoto, M. Yamada, S. Yamada, K. Kuwano, and Y. Nakanishi The Role of High Mobility Group Box1 in Pulmonary Fibrosis Am. J. Respir. Cell Mol. Biol., October 1, 2008; 39(4): 440 - 447. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. Kitahara, Y. Takeishi, M. Harada, T. Niizeki, S. Suzuki, T. Sasaki, M. Ishino, O. Bilim, O. Nakajima, and I. Kubota High-mobility group box 1 restores cardiac function after myocardial infarction in transgenic mice Cardiovasc Res, October 1, 2008; 80(1): 40 - 46. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. M. Alleva, A. C. Budd, and I. A. Clark Systemic Release of High Mobility Group Box 1 Protein during Severe Murine Influenza J. Immunol., July 15, 2008; 181(2): 1454 - 1459. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Sha, J. Zmijewski, Z. Xu, and E. Abraham HMGB1 Develops Enhanced Proinflammatory Activity by Binding to Cytokines J. Immunol., February 15, 2008; 180(4): 2531 - 2537. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Ponsuksili, E. Murani, C. Walz, M. Schwerin, and K. Wimmers Pre- and postnatal hepatic gene expression profiles of two pig breeds differing in body composition: insight into pathways of metabolic regulation Physiol Genomics, May 11, 2007; 29(3): 267 - 279. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. Yang, Q. Chen, H. Yang, K. J. Tracey, M. Bustin, and J. J. Oppenheim High mobility group box-1 protein induces the migration and activation of human dendritic cells and acts as an alarmin J. Leukoc. Biol., January 1, 2007; 81(1): 59 - 66. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. W. Bell, W. Jiang, C. F. Reich III, and D. S. Pisetsky The extracellular release of HMGB1 during apoptotic cell death Am J Physiol Cell Physiol, December 1, 2006; 291(6): C1318 - C1325. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K Volp, M-L Brezniceanu, S Bosser, T Brabletz, T Kirchner, D Gottel, S Joos, and M Zornig Increased expression of high mobility group box 1 (HMGB1) is associated with an elevated level of the antiapoptotic c-IAP2 protein in human colon carcinomas Gut, February 1, 2006; 55(2): 234 - 242. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Kurosaka, Q. Chen, F. Yarovinsky, J. J. Oppenheim, and D. Yang Mouse Cathelin-Related Antimicrobial Peptide Chemoattracts Leukocytes Using Formyl Peptide Receptor-Like 1/Mouse Formyl Peptide Receptor-Like 2 as the Receptor and Acts as an Immune Adjuvant J. Immunol., May 15, 2005; 174(10): 6257 - 6265. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. Schlueter, H. Weber, B. Meyer, P. Rogalla, K. Roser, S. Hauke, and J. Bullerdiek Angiogenetic Signaling through Hypoxia: HMGB1: An Angiogenetic Switch Molecule Am. J. Pathol., April 1, 2005; 166(4): 1259 - 1263. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. Jiang and D. S. Pisetsky The effect of inflammation on the generation of plasma DNA from dead and dying cells in the peritoneum J. Leukoc. Biol., March 1, 2005; 77(3): 296 - 302. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. Kalinina, A. Agrotis, Y. Antropova, G. DiVitto, P. Kanellakis, G. Kostolias, O. Ilyinskaya, E. Tararak, and A. Bobik Increased Expression of the DNA-Binding Cytokine HMGB1 in Human Atherosclerotic Lesions: Role of Activated Macrophages and Cytokines Arterioscler. Thromb. Vasc. Biol., December 1, 2004; 24(12): 2320 - 2325. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. Yang, Q. Chen, H. F. Rosenberg, S. M. Rybak, D. L. Newton, Z. Y. Wang, Q. Fu, V. T. Tchernev, M. Wang, B. Schweitzer, et al. Human Ribonuclease A Superfamily Members, Eosinophil-Derived Neurotoxin and Pancreatic Ribonuclease, Induce Dendritic Cell Maturation and Activation J. Immunol., November 15, 2004; 173(10): 6134 - 6142. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 I. A. Clark, L. M. Alleva, A. C. Mills, and W. B. Cowden Pathogenesis of Malaria and Clinically Similar Conditions Clin. Microbiol. Rev., July 1, 2004; 17(3): 509 - 539. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. S. Park, D. Svetkauskaite, Q. He, J.-Y. Kim, D. Strassheim, A. Ishizaka, and E. Abraham Involvement of Toll-like Receptors 2 and 4 in Cellular Activation by High Mobility Group Box 1 Protein J. Biol. Chem., February 27, 2004; 279(9): 7370 - 7377. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. J. H. Chu and M. L. Ng The mechanism of cell death during West Nile virus infection is dependent on initial infectious dose J. Gen. Virol., December 1, 2003; 84(12): 3305 - 3314. [Abstract] [Full Text] [PDF]
|
|
