High-mobility group box 1 protein (HMGB1): Nuclear weapon in the immune arsenal

Nature Reviews Immunology

Volumn 5, Issue 4, 2005, Pages 331-342

  Lotze, Michael T ^a   Tracey, Kevin J ^b  

^a UNIVERSITY OF PITTSBURGH SCHOOL OF MEDICINE   (United States)

^b Institute of Medical Research   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

HIGH MOBILITY GROUP B1 PROTEIN; PROTEIN RAGE; PROTEIN S 100; UNCLASSIFIED DRUG;

APOPTOSIS; ARTHRITIS; BLEEDING; BURN; CANCER; CROHN DISEASE; GENETIC TRANSCRIPTION; HUMAN; IMMUNITY; INFECTION; INFLAMMATION; INJURY; NONHUMAN; PRIORITY JOURNAL; PROTEIN BINDING; PROTEIN EXPRESSION; PROTEIN FUNCTION; PROTEIN SECRETION; PROTEIN STRUCTURE; REVIEW; SEPSIS; SIGNAL TRANSDUCTION;

AMINO ACID SEQUENCE; ANIMALS; ANTIGENS, NEOPLASM; CELL NUCLEUS; HMGB1 PROTEIN; HUMANS; IMMUNE SYSTEM; MEMBRANE GLYCOPROTEINS; MITOGEN-ACTIVATED PROTEIN KINASES; MOLECULAR SEQUENCE DATA; RECEPTORS, CELL SURFACE; SIGNAL TRANSDUCTION; TOLL-LIKE RECEPTORS;

EID: 17144376810     PISSN: 14741733     EISSN: None     Source Type: Journal    
DOI: 10.1038/nri1594     Document Type: Review

References (137)

1. Wang, H., Czura, C. & Tracey, K. J. in The Cytokine Handbook 4th edn, Vol. 2 (eds Thomson, A. W. & Lotze, M. T.) 913-926 (Elsevier, London, 2003).
2. Tracey, K. Fatal Sequence: The Killer Within (Dana, New York, 2005).
3. Reimold, A. M. TNFα as therapeutic target: new drugs, more applications. Curr. Drug Targets Inflamm. Allergy 1, 377-392 (2002).
4. Cohen, S. B. et al. A multicentre, double blind, randomised, placebo controlled trial of anakinra (Kineret), a recombinant interleukin 1 receptor antagonist, in patients with rheumatoid arthritis treated with background methotrexate. Ann. Rheum. Dis. 63, 1062-1068 (2004).
5. Rosenberg, S. A. et al. Combination therapy with interleukin-2 and α-interferon for the treatment of patients with advanced cancer. J. Clin. Oncol. 7, 1863-1874 (1989).
6. Lotze, M. T. et al. In vivo administration of purified human interleukin 2. II. Half life, immunologic effects, and expansion of peripheral lymphoid cells in vivo with recombinant IL 2. J. Immunol. 135, 2865-2875 (1985). This paper describes the initial clinical demonstration of the effects of IL-2 in promoting novel cytokine-associated symptoms and disorders, antitumour effects and increased numbers of circulating T cells and eosinophils.
7. Lotze, M. T., Frana, L. W., Sharrow, S. O., Robb, R. J. & Rosenberg, S. A. In vivo administration of purified human interleukin 2.1. Half-life and immunologic effects of the Jurkat cell line-derived interleukin 2. J. Immunol. 134, 157-166 (1985).
8. Atkins, M. B. et al. High-dose recombinant interleukin 2 therapy for patients with metastatic melanoma: analysis of 270 patients treated between 1985 and 1993. J. Clin. Oncol. 17, 2105-2116 (1999).
9. Tahourdin, C. S. & Bustin, M. Chromatin subunits elicit species-specific antibodies against nucleoprotein antigenic determinants. Biochemistry 19, 4387-4394 (1980).
10. Laudet, V., Stehelin, D. & Clevers, H. Ancestry and diversity of the HMG box superfamily. Nucleic Acids Res. 21, 2493-2501 (1993).
11. Wu, Q., Zhang, W., Pwee, K. H. & Kumar, P. P. Rice HMGB1 protein recognizes DNA structures and bends DNA efficiently. Arch. Biochem. Biophys. 411, 105-111 (2003).
12. Javaherian, K., Liu, J. F. & Wang, J. C. Nonhistone proteins HMG1 and HMG2 change the DNA helical structure. Science 199, 1345-1346 (1978).
13. Bustin, M., Hopkins, R. B. & Isenberg, I. Immunological relatedness of high mobility group chromosomal proteins from calf thymus. J. Biol. Chem. 253, 1694-1699 (1978). This was one of the first papers to define HMGB1, clearly distinguishing it from histones and then showing that it potentially had a non-nuclear role.
14. Baker, C., Isenberg, I., Goodwin, G. H. & Johns, E. W. Physical studies of the nonhistone chromosomal proteins HMG-U and HMG-2. Biochemistry 15, 1645-1649 (1976).
15. West, K. L., Castellini, M. A., Duncan, M. K. & Bustin, M. Chromosomal proteins HMGN3a and HMGN3b regulate the expression of glycine transporter 1. Mol. Cell. Biol. 24, 3747-3756 (2004).
16. Park, J. S. et al. Actuation of gene expression in human neutrophils by high mobility group box 1 protein. Am. J. Physiol. Cell Physiol. 284, C870-C879 (2003).
17. Stras, M., Ozaki, T., Bacikova, A., Kageyama, H. & Nakagawara, A. HMGB1 and HMGB2 cell-specifically down-regulate the p53- and p73-dependent sequence-specific transactivation from the human Bax gene promoter. J. Biol. Chem. 277, 7157-7164 (2002).
18. Bonaldi, T. et al. Monocytic cells hyperacetylate chromatin protein HMGB1 to redirect it towards secretion. EMBO J. 22, 5551-5560 (2003). This study showed that a shift from deacetylation to acetylation of HMGB1 is associated with disguising nuclear-localization signals, thereby allowing emigration into secretory vesicles in monocyte and macrophage cell lines. The authors suggested that up to 100,000 variants of HMGB1 are possible, given that up to 43 lysine residues could be differentially acetylated.
19. Wang, H. et al. HMG-1 as a late mediator of endotoxin lethality in mice. Science 285, 248-251 (1999). This is the initial paper from K.J.T. and colleagues showing that late mediators (after TNF and IL-1) of LPS-induced death in mice were associated with HMGB1 release. Animals could be rescued by treatment with HMGB1-specific antibodies, and patients who were dying of sepsis in intensive care had higher serum levels of HMGB1 than survivors of sepsis.
20. Semino, C., Angelini, G., Poggi, A. & Rubartelli, A. NK/iDC Interaction results in IL-18 secretion by DCs at the synaptic cleft followed by NK cell activation and release of the DC maturation factor HMGB1. Blood (in the press). The crucial interaction between NK cells and DCs has been recognized for several years. This study shows an important role for IL-18 and HMGB1 at the immunological synapse that is formed between these cells.
21. Seong, S. Y. & Matzinger, P. Hydrophobicity: an ancient damage-associated molecular pattern that initiates innate immune responses. Nature Rev. Immunol. 4, 469-478 (2004).
22. Zeh, H. J. & Lotze, M. T. Addicted to death: invasive cancer and the immune response to unscheduled cell death. J. Immunother. 28, 1-9 (2005). In this paper, a provocative theory is advanced. The authors suggest that cancer is essentially a disorder of cell death rather than cell growth and is driven by the release of necrotic products such as HMGB1.
23. Pasqualini, J. R., Sterner, R., Mercat, P. & Allfrey, V. G. Estradiol enhanced acetylation of nuclear high mobility group proteins of the uterus of newborn guinea pigs. Biochem. Biophys. Res. Commun. 161, 1260-1266 (1989).
24. Prendergast, P., Onate, S. A., Christensen, K. & Edwards, D. P. Nuclear accessory factors enhance the binding of progesterone receptor to specific target DNA. J. Steroid Biochem. Mol. Biol. 48, 1-13 (1994).
25. Zhang, C. C., Krieg, S. & Shapiro, D. J. HMG-1 stimulates estrogen response element binding by estrogen receptor from stably transfected HeLa cells. Mol. Endocrinol. 13, 632-643 (1999).
26. Ciubotaru, M. & Schatz, D. G. Synapsis of recombination signal sequences located in cis and DNA underwinding in V(D)J recombination. Mol. Cell. Biol. 24, 8727-8744 (2004).
27. Zong, W. X., Ditsworth, D., Bauer, D. E., Wang, Z. Q. & Thompson, C. B. Akylating DNA damage stimulates a regulated form of necrotic cell death. Genes Dev. 18, 1272-1282 (2004).
28. Stros, M., Muselikova-Polanska, E., Pospisilova, S. & Strauss, F. High-affinity binding of tumor-suppressor protein p53 and HMGB1 to hemicatenated DNA loops. Biochemistry 43, 7215-7225 (2004).
29. Zayed, H., Izsvak, Z., Khare, D., Heinemann, U. & Ivics, Z. The DNA-bending protein HMGB1 is a cellular cofactor of Sleeping Beauty transposition. Nucleic Acids Res. 31, 2313-2322 (2003).
30. Knapp, S. et al. The long acidic tail of high mobility group box 1 (HMGB1) protein forms an extended and flexible structure that interacts with specific residues within and between the HMG boxes. Biochemistry 43, 11992-11997 (2004).
31. Alexandrova, E. A. & Bettchev, B. G. Differences between HMG1 proteins isolated from normal and tumour cells. Biochim. Biophys. Acta 915, 399-405 (1987).
32. Kohlstaedt, L. A. & Cole, R. D. Specific interaction between H1 histone and high mobility protein HMG1. Biochemistry 33, 570-575 (1994).
33. Betermier, M., Rousseau, P., Alazard, R. & Chandler, M. Mutual stabilisation of bacteriophage μ repressor and histone-like proteins in a nucleoprotein structure. J. Mol. Biol. 249, 332-341 (1995).
34. Costello, E., Saudan, P., Winocour, E., Pizer, L. & Beard, P. High mobility group chromosomal protein 1 binds to the adeno-associated virus replication protein (Rep) and promotes Rep-mediated site-specific cleavage of DNA, ATPase activity and transcriptional repression. EMBO J. 16, 5943-5954 (1997).
35. Chu, J. J. & Ng, M. L. The mechanism of cell death during West Nile virus infection is dependent on initial infectious dose. J. Gen. Virol. 64, 3305-3314 (2003).
36. Kamitani, W. et al. Borna disease virus phosphoprotein binds a neurite outgrowth factor, amphoterin/HMG-1. J. Virol. 75, 8742-8751 (2001).
37. Hindmarsh, P. et al. HMG protein family members stimulate human immunodeficiency virus type 1 and avian sarcoma virus concerted DMA integration in vitro. J. Virol. 73, 2994-3003 (1999).
38. Kajino, K. et al. Recombination hot spot of hepatitis B virus genome binds to members of the HMG domain protein family and the Y box binding protein family; implication of these proteins in genomic instability. Intervirology 44, 311-316 (2001).
39. Naghavi, M. H. et al. Intracellular high mobility group B1 protein (HMGB1) represses HIV-1 LTR-directed transcription in a promoter- and cell-specific manner. Virology 314, 179-189 (2003).
40. Zhang, G. et al. Borna disease virus phosphoprotein represses p53-mediated transcriptional activity by interference with HMGB1. J. Virol. 77, 12243-12251 (2003).
41. Yang, H. et al. Reversing established sepsis with antagonists of endogenous high-mobility group box 1. Proc. Natl Acad. Sci. USA 101, 296-301 (2004).
42. Wang, H., Czura, C. J. & Tracey, K. J. Lipid unites disparate syndromes of sepsis. Nature Med. 10, 124-125 (2004).
43. Andersson, U. & Erlandsson-Harris, H. HMGB1 is a potent trigger of arthritis. J. Intern. Med. 255, 344-350 (2004). This paper describes the first evidence that inhibition of HMGB1 reverses established experimentally induced arthritis. It is probable that this approach will be tested in clinical trials of patients with rheumatoid arthritis.
44. Park, J. S. et al. Involvement of Toll-like receptors 2 and 4 in cellular activation by high mobility group box 1 protein. J. Biol. Chem. 279, 7370-7377 (2004). This study was the first to show that there are receptors for HMGB1 other than RAGE. These receptors are particularly important for neutrophil recruitment and activation.
45. + T lymphocytes induce polarized exocytosis of secretory lysosomes by dendritic cells with release of interleukin-1β and cathepsin D. Blood 98, 2152-2159 (2001).
46. Gardella, S. et al. The nuclear protein HMGB1 is secreted by monocytes via a non-classical, vesicle-mediated secretory pathway. EMBO Rep. 3, 995-1001 (2002).
47. Zhang, X. D., Gillespie, S. K., Borrow, J. M. & Hersey, P. The histone deacetylase inhibitor suberic bishydroxamate regulates the expression of multiple apoptotic mediators and induces mitochondria-dependent apoptosis of melanoma cells. Mol. Cancer Ther. 3, 425-435 (2004).
48. Fu, M., Wang, C., Zhang, X. & Pestell, R. G. Acetylation of nuclear receptors in cellular growth and apoptosis. Biochem. Pharmacol. 68, 1199-1208 (2004).
49. Kalinina, N. et al. Increased expression of the DNA-binding cytokine HMGB1 in human atherosclerotic lesions. Role of activated macrophages and cytokines. Arterioscler. Thromb. Vasc. Biol. 24, 2320-2325 (2004).
50. Chen, G. et al. Bacterial endotoxin stimulates macrophages to release HMGB1 partly through CD14- and TNF-dependent mechanisms. J. Leukoc. Biol. 76, 994-1001 (2004).
51. Scaffidi, P., Misteli, T. & Bianchi, M. E. Release of chromath protein HMGB1 by necrotic cells triggers inflammation. Nature 418, 191-195 (2002). This is a remarkable paper showing that HMGB1 release distinguishes necrotic cell death from apoptotic cell death, the latter being associated with tight sequestration of HMGB1 in the nucleus. Blocking HMGB1 release prevented paracetamol-associated necrosis and inflammation.
52. Rovere-Querini, P. et al. HMGB1 is an endogenous immune adjuvant released by necrotic cells. EMBO Rep. 5, 825-830 (2004). The Bianchi group has been a leader in the HMGB1 field since they first identified HMGB1 as a protein that binds cruciform DNA in the nucleus. This paper describes the adjuvant properties of HMGB1 that is released from necrotic cells or is administered as a recombinant protein.
53. Merenmies, J., Pihlaskari, R., Laitinen, J., Wartiovaara, J. & Rauvala, H. 30-kDa Heparin-binding protein of brain (amphoterin) involved in neurite outgrowth. Amino acid sequence and localization in the filopodia of the advancing plasma membrane. J. Biol. Chem. 266, 16722-16729 (1991).
54. Calogero, S. et al. The lack of chromosomal protein Hmg1 does not disrupt cell growth but causes lethal hypoglycaemia in newborn mice. Nature Genet. 22, 276-280 (1999).
55. Liu, H., Yao, Y. M., Dong, Y. Q., Yu, Y. & Sheng, Z. Y. High mobility group box-1 protein activates Janus kinase-signal transducer and activator of transcription pathway in rat peritoneal macrophages. Zhongguo Wei Zhong Bing Ji Jiu Yi Xue 16, 592-595 (2004) (in Chinese).
56. Bottger, M. et al. Condensation of vector DNA by the chromosomal protein HMG1 results in efficient transfection. Biochim. Biophys. Acta 950, 221-228 (1988).
57. Bottger, M., Platzer, M., Messung, U. & Strauss, M. Transfection by DNA-nuclear protein HMG1 complexes: raising of efficiency and role of DNA topology. Arch. Geschwulstforsch 60, 265-270 (1990) (in German).
58. Tomita, N. et al. Direct in vivo gene introduction into rat kidney. Biochem. Biophys. Res. Commun. 186, 129-134 (1992).
59. Ellison, K. E. et al. Fusigenic liposome-mediated DNA transfer into cardiac myocytes. J. Mol. Cell. Cardiol. 28, 1385-1399 (1996).
60. Mistry, A. R. et al. Recombinant HMG1 protein produced in Pichia pastoris: a nonviral gene delivery agent. Biotechniques 22, 716-729 (1997).
61. Rubartelli, A. & Sitia, R. Entry of exogenous polypeptides into the nucleus of living cells: facts and speculations. Trends Cell Biol. 5, 409-412 (1995). This is an early summary of the role of protein-transduction domains, which enable proteins to traverse various cell membranes.
62. Dietz, G. P. & Bdeltahr, M. Delivery of bioactive molecules into the cell: the Trojan horse approach. Mol. Cell. Neurosci. 27, 85-131 (2004).
63. Persson, D., Thoren, P. E., Lincoln, P. & Norden, B. Vesicle membrane interactions of penetratin analogues. Biochemistry 43, 11045-11055 (2004).
64. Werman, A. et al. The precursor form of IL-1α is an intracrine proinflammatory activator of transcription. Proc. Natl Acad. Sci. USA 101, 2434-2439 (2004).
65. Re, R. N. The intracrine hypothesis and intracellular peptide hormone action. Bioessays 25, 401-409 (2003). The idea that proteins could have a crucial role as both endocrine agents and nuclear modulators of transcription presaged the identification of HMGB1 and IL-1 as exemplars of this theory.
66. Ryckman, C., Vandal, K., Rouleau, P., Talbot, M. & Tessier, P. A. Proinflammatory activities of S100: proteins S100A8, S100A9, and S100A8/A9 induce neutrophil chemotaxis and adhesion. J. Immunol. 170, 3233-3242 (2003).
67. Schnurr, M. et al. ATP gradients inhibit the migratory capacity of specific human dendritic cell types: implications for P2Y11 receptor signaling. Blood 102, 613-620 (2003). The idea that secreted or released ATP might function as a PAMP, promoting both immune reactivity and activation and/or maturation of myeloid DCs - as was subsequently shown for S100 molecules, uric acid and HMGB1 - defines a new criterion for PAMPs.
68. Shi, Y., Evans, J. E. & Rock, K. L. Molecular identification of a danger signal that alerts the immune system to dying cells. Nature 425, 516-521 (2003). The immunogenicity and adjuvanticity of lysed cells has previously been recognized. That it might include the small purine metabolite uric acid had not been recognized until this paper was published. Similar to HMGB1, uric acid promotes the maturation of myeloid DCs.
69. Chavakis, T., Bierhaus, A. & Nawroth, P. P. RAGE (receptor for advanced glycation end products): a central player in the inflammatory response. Microbes Infect. 6, 1219-1225 (2004).
70. Treutiger, C. J. et al. High mobility group 1 B-box mediates activation of human endothelium. J. Intern. Med. 254, 375-385 (2003).
71. Chavakis, T. et al. The pattern recognition receptor (RAGE) is a counterreceptor for leukocyte integrins: a novel pathway for inflammatory cell recruitment. J. Exp. Med. 198, 1507-1515 (2003). In this paper, it was proposed that rapid recruitment of inflammatory cells to sites of tissue damage or injury is associated with the interaction between RAGE and leukocyte integrins that interact with RAGE ligands, such as S100 and HMGB1.
72. Fiuza, C. et al. Inflammation-promoting activity of HMGB1 on human microvascular endothelial cells. Blood 101, 2652-2660 (2003).
73. Rouhiainen, A. et al. Regulation of monocyte migration by amphoterin (HMGB1). Blood 104, 1174-1182 (2004).
74. Palumbo, R. et al. Extracellular HMGB1, a signal of tissue damage, induces mesoangioblast migration and proliferation. J. Cell Biol. 164, 441-449 (2004). This paper reports that HMGB1 recruits mesenchymal and haematopoietic stem cells to sites of tissue damage or injury, which is potentially important for tissue-engineering strategies.
75. Sappington, P. L. et al. HMGB1 B box increases the permeability of Caco-2 enterocytic monolayers and impairs intestinal barrier function in mice. Gastroenterology 123, 790-802 (2002). Perhaps one of the most crucial aspects of epithelial injury is the rapid need to re-establish barrier function and to recruit inflammatory cells for immune or repair functions. This paper showed that HMGB1 has an important role in these functions in the gut.
76. Palumbo, R. & Blanchi, M. E. High mobility group box 1 protein, a cue for stem cell recruitment. Biochem. Pharmacol. 68, 1166-1170 (2004).
77. Demarco, R. A., Fink, M. P. & Lotze, M. T. Monocytes promote natural killer cell Interferon γ production in response to the endogenous danger signal HMGB1. Mol. Immunol. 42, 433-444 (2005).
78. H1 polarization. J. Immunol. 173, 307-313 (2004).
79. Albert, M. L., Sauter, B. & Bhardwaj, N. Dendritic cells acquire antigen from apoptotic cells and induce class I-restricted CTLs. Nature 392, 86-89 (1998).
80. Wertheimer, A. M., Bakke, A. & Rosen, H. R. Direct enumeration and functional assessment of circulating dendritic cells in patients with liver disease. Hepatology 40, 335-345 (2004).
81. Wang, Y. H. & Liu, Y. J. Mysterious origin of plasmacytoid dendritic cell precursors. Immunity 21, 1-2 (2004).
82. van der Molen, R. G. et al. Functional impairment of myeloid and plasmacytoid dendritic cells of patients with chronic hepatitis B. Hepatology 40, 738-746 (2004).
83. Gill, M. A. et al. Blood dendritic cells and DC-poietins in systemic lupus erythematosus. Hum. Immunol. 63, 1172-1180 (2002).
84. Arpinati, M. et al. Role of plasmacytoid dendritic cells in immunity and tolerance after allogeneic hematopoietic stem cell transplantation. Transpl. Immunol. 11, 345-356 (2003).
85. Hartmann, E. et al. Identification and functional analysis of tumor-infiltrating plasmacytoid dendritic cells in head and neck cancer. Cancer Res. 63, 6478-6487 (2003).
86. Mazariegos, G. V. et al. Dendritic cell subset ratio in peripheral blood correlates with successful withdrawal of immunosuppression in liver transplant patients. Am. J. Transplant. 3, 689-696 (2003).
87. Vermi, W. et al. Recruitment of immature plasmacytoid dendritic cells (plasmacytoid monocytes) and myeloid dendritic cells in primary cutaneous melanomas. J. Pathol. 200, 255-268 (2003).
88. + regulatory T cells. J. Immunol. 173, 4433-4442 (2004).
89. Shirasawa, M. et al. Receptor for advanced glycation end-products is a marker of type I lung alveolar cells. Genes Cells 9, 165-174 (2004).
90. Fehrenbach, H. et al. Receptor for advanced glycation endproducts (RAGE) exhibits highly differential cellular and subcellular localisation in rat and human lung. Cell. Mol. Biol. (Noisy-le-grand) 44, 1147-1157 (1998).
91. Katsuoka, F. et al. Type II alveolar epithelial cells in lung express receptor for advanced glycation end products (RAGE) gene. Biochem. Biophys. Res. Commun. 238, 512-516 (1997).
92. Lutz, W. & Stetkiewicz, J. High mobility group box 1 protein as a late-acting mediator of acute lung inflammation. Int. J. Occup. Med. Environ. Health 17, 245-254 (2004).
93. Ueno, H. et al. Contributions of high mobility group box protein in experimental and clinical acute lung injury. Am. J. Respir. Crit. Care Med. 170, 1310-1316 (2004).
94. Hanford, L. E. et al. Purification and characterization of mouse soluble receptor for advanced glycation end products (sRAGE). J. Biol. Chem. 279, 50019-50024 (2004).
95. Hanford, L. E. et al. Regulation of receptor for advanced glycation end products during bleomycin-induced lung injury. Am. J. Respir. Cell Mol. Biol. 29, S77-S81 (2003).
96. Grigorov, I., Milosavljevic, T., Cvetkovic, I. & Petrovic, M. HMG-1 as regulatory trans-acting protein in the acute phase-induced expression of the rat liver haptoglobin gene. Gen. Physiol. Biophys. 20, 401-412 (2001).
97. Fang, W. H. et al. The significance of changes in high mobility group-1 protein mRNA expression in rats after thermal injury. Shock 17, 329-333 (2002).
98. Ito, I. et al. Conformational difference in HMGB1 proteins of human neutrophils and lymphocytes revealed by epitope mapping of a monoclonal antibody. J. Biochem. (Tokyo) 136, 155-162 (2004).
99. Tsung A., et al. High-mobility group box 1 (HMGB1) mediates hepatic injury following murine liver ischemia-reperfusion. J. Exp. Med. (in the press).
100. Cataldegirmen, G. et al. RAGE limits regeneration after massive liver injury by coordinated suppression of TNF-α and NF-κB. J. Exp. Med. 201, 473-484 (2005).
101. Zeng, S. et al. Blockade of receptor for advanced glycation end product (RAGE) attenuates ischemia and reperfusion injury to the liver in mice. Hepatology 39, 422-432 (2004).
102. Chou, D. K., Zhang, J., Smith, F. I., McCaffery P. & Jungalwala, F. B. Developmental expression of receptor for advanced glycation end products (RAGE), amphoterin and sulfoglucuronyl (HNK-1) carbohydrate in mouse cerebellum and their role in neurite outgrowth and cell migration. J. Neurochem. 90, 1389-1401 (2004).
103. Takata, K. et al. High mobility group box protein-1 inhibits miorogial Aβ clearance and enhances Aβ neurotoxicity. J. Neurosci. Res. 78, 880-891 (2004).
104. Agnello, D., Wang, H., Yang, H., Tracey, K. J. & Ghezzi, P. HMGB-1, a DNA-binding protein with cytokine activity, induces brain TNF and IL-6 production, and mediates anorexia and taste aversion. Cytokine 18, 231-236 (2002).
105. O'Connor, K. A. et al. Further characterization of high mobility group box 1 (HMGB1) as a proinflammatory cytokine: central nervous system effects. Cytokine 24, 254-265 (2003).
106. Wang, H. et al. Cholinergic agonists inhibit HMGB1 release and improve survival in experimental sepsis. Nature Med. 10, 1216-1221 (2004).
107. Sappington, P. L., Fink, M. E., Yang, R., Delude, R. L. & Fink, M. P. Ethyl pyruvate provides durable protection against inflammation-induced intestinal epithelial barrier dysfunction. Shock 20, 521-528 (2003).
108. Wang, H., Yang, H. & Tracey, K. J. Extracellular role of HMGB1 in inflammation and sepsis. J. Intern. Med. 255, 320-331 (2004).
109. Czura, C. J., Yang, H., Amella, C. A. & Tracey, K. J. HMGB1 in the immunology of sepsis (not septic shock) and arthritis. Adv. Immunol. 84, 181-200 (2004).
110. Ombrellino, M. et al. Increased serum concentrations of high-mobility-group protein 1 in haemorrhagic shock. Lancet 354, 1446-1447 (1999).
111. Kim, J. Y. et al. HMGB1 contributes to the development of acute lung injury after hemorrhage. Am. J. Physiol. Lung Cell. Mol. Physiol. 7 Jan 2005 (doi:10.1152/ajplung.00359.2004).
112. Jungas, T., Verbeke, P., Darville, T. & Ojcius, D. M. Cell death, BAX activation, and HMGB1 release during infection with Chlamydia. Microbes Infect. 6, 1145-1155 (2004).
113. Kokkola, R. et al. High mobility group box chromosomal protein 1: a novel proinflammatory mediator in synovitis. Arthritis Rheum, 46, 2598-2603 (2002).
114. Kokkola, R. et al. Successful treatment of collagen-induced arthritis in mice and rats by targeting extracellular high mobility group box chromosomal protein 1 activity. Arthritis Rheum. 48, 2052-2058 (2003).
115. Flohr, A. M. et al. Variation of HMGB1 expression in breast cancer. Anticancer Res. 21, 3881-3885 (2001).
116. Huttunen, H. J., Pages, C., Kuja-Panula, J., Ridley, A. J. & Rauvala, H. Receptor for advanced glycation end products-binding COOH-terminal motif of amphoterin inhibits invasive migration and metastasis. Cancer Res. 62, 4805-4811 (2002).
117. Choi, Y. R. et al. Overexpression of high mobility group box 1 in gastrointestinal stromal tumors with K/T mutation. Cancer Res. 63, 2188-2193 (2003).
118. Kuniyasu, H. et al. Expression of receptors for advanced glycation end-products (RAGE) is closed associated with the invasive and metastatic activity of gastric cancer. J. Pathol. 196, 163-170 (2002).
119. Guazzi, S., Strangio, A., Franzi, A. T. & Bianchi, M. E. HMGB1, an architectural chromatin protein and extracellular signalling factor, has a spatially and temporally restricted expression pattern in mouse brain. Gene Expr. Patterns 3, 29-33 (2003).
120. Kuniyasu, H., Chihara, Y. & Takahashi, T. Co-expression of receptor for advanced glycation end products and the ligand amphoterin associates closely with metastasis of colorectal cancer. Oncol Rep. 10, 445-448 (2003).
121. Kuniyasu, H., Chihara, Y. & Kondo, H. Differential effects between amphoterin and advanced glycation end products on colon cancer cells. Int. J. Cancer 104, 722-727 (2003).
122. Lotze, M. T. & DeMarco, R. A. Dealing with death: HMGB1 as a novel target for cancer therapy. Curr. Opin. Investig. Drugs 4, 1405-1409 (2003).
123. Meyer, B. et al. Expression pattern of the HMGB1 gene in sarcomas of the dog. Anticancer Res. 24, 707-710 (2004).
124. Yuan, F., Gu, L., Quo, S., Wang, C. & Li, G. M. Evidence for involvement of HMGB1 protein in human DNA mismatch repair. J. Biol. Chem. 279, 20935-20940 (2004).
125. Emberley, E. D., Murphy, L. C. & Watson, P. H. S100A7 and the progression of breast cancer. Breast Cancer Res. 6, 153-159 (2004).
126. Harpio, R. & Einarsson, R. S100 proteins as cancer biomarkers with focus on S100B in malignant melanoma. Clin. Biochem. 37, 512-518 (2004).
127. Taguchi, A. et al. Blockade of RAGE-amphoterin signalling suppresses tumour growth and metastases. Nature 405, 354-360 (2000). Although HMGB1 has been found to be expressed together with RAGE in many human tumours and although this is associated with poor prognosis, the means by which this occurs was not determined until this study was carried out. Enhancement of tumour growth was found to occur through forced expression of RAGE, and its inhibition through expression of a truncated RAGE molecule or through soluble RAGE.
128. Falzoni, S., Chiozzi, P., Ferrari, D., Buell, G. & Di Virgilio, F. P2X, receptor and polykarion formation. Mol. Biol. Cell 11, 3169-3176 (2000).
129. Houghton, J. et al. Gastric cancer originating from bone marrow-derived cells. Science 306, 1568-1571 (2004).
130. Ishihara, K., Tsutsumi, K., Kawane, S., Nakajima, M. & Kasaoka, T. The receptor for advanced glycation end-products (RAGE) directly binds to ERK by a D-domain-like docking site. FEBS Lett. 550, 107-113 (2003).
131. Huttunen, H. J., Fages, C. & Rauvala, H. Receptor for advanced glycation end products (RAGE)-mediated neurite outgrowth and activation of NF-κB require the cytoplasmic domain of the receptor but different downstream signaling pathways. J. Biol. Chem. 274, 19919-19924 (1999).
132. Huttunen, H. J., Kuja-Panula, J. & Rauvala, H. Receptor for advanced glycation end products (RAGE) signaling induces CREB-dependent chromogranin expression during neuronal differentiation. J. Biol. Chem. 277, 38635-38646 (2002).
133. ras-dependent mitogen-activated protein kinase pathway regulated by oxidant stress. J. Biol. Chem. 272, 17810-17814 (1997).
134. Sakaguchi, T. et al. Central role of RAGE-dependent neointimal expansion in arterial restenosis. J. Clin. Invest. 111, 959-972 (2003).
135. Rong, L. L et al. RAGE modulates peripheral nerve regeneration via recruitment of both inflammatory and axonal outgrowth pathways. FASEB J. 18, 1818-1825 (2004).
136. Takada, M., Hirata, K., Ajiki, T., Suzuki, Y. & Kuroda, Y. Expression of receptor for advanced glycation end products (RAGE) and MMP-9 in human pancreatic cancer cells. Hepatogastroenterology 51, 928-930 (2004).
137. Kokkola, R. et al. RAGE is the major receptor for the proinflammatory activity of HMGB1 in rodent macrophages. Scand. J. Immunol. 61, 1-9 (2005).