Yonsei Med J.  2014 Sep;55(5):1165-1176. 10.3349/ymj.2014.55.5.1165.

The Role of High Mobility Group Box 1 in Innate Immunity

• Lee SA
• Kwak MS
• Kim S
• Shin JS

• KMID: 1799478
• DOI: http://doi.org/10.3349/ymj.2014.55.5.1165

Abstract

With growing accounts of inflammatory diseases such as sepsis, greater understanding the immune system and the mechanisms of cellular immunity have become primary objectives in immunology studies. High mobility group box 1 (HMGB1) is a ubiquitous nuclear protein that is implicated in various aspects of the innate immune system as a damage-associated molecular pattern molecule and a late mediator of inflammation, as well as in principal cellular processes, such as autophagy and apoptosis. HMGB1 functions in the nucleus as a DNA chaperone; however, it exhibits cytokine-like activity when secreted by injurious or infectious stimuli. Extracellular HMGB1 acts through specific receptors to promote activation of the NF-kappaB signaling pathway, leading to production of cytokines and chemokines. These findings further implicate HMGB1 in lethal inflammatory diseases as a crucial regulator of inflammatory, injurious, and infectious responses. In this paper, we summarize the role of HMGB1 in inflammatory and non-inflammatory states and assess potential therapeutic approaches targeting HMGB1 in inflammatory diseases.

Keyword

HMGB1; DAMP; inflammation; innate immunity

MeSH Terms

Amino Acid Sequence
HMGB1 Protein/chemistry/metabolism/*physiology
Humans
Immunity, Innate/*physiology
*Models, Immunological
Molecular Sequence Data
Protein Structure, Tertiary
Signal Transduction
HMGB1 Protein

Figure

• 

  Fig. 1 Structure of HMGB1. (A) HMGB1 protein is composed of 215 amino acids in three structural domains: the A box (1-79), B box (89-162), and the acidic C tail (186-215). The A box functions in DNA binding and inducing anti-inflammatory effects, whereas the B box domain plays an important role in DNA binding and stimulating proinflammatory responses. The B box domain consists of two crucial binding sites for TLR4 and RAGE that mediate the release of proinflammatory cytokines. In particular, the 20 amino acids of the TLR4 binding site (89-108) are the minimal sequence needed to induce cytokine activity. Two peptide regions (3-15, 80-96) of HMGB1 bind to delipidated LPS and lipid A regions, respectively. (B) The functional component of HMGB1 is represented in a linear diagram underlining the amino acid residues that constitute the A box domain (pink), B box domain (purple), and C tail (blue). Symbols are used to denote specific sites for the four post-translational modifications that HMGB1 goes through during active secretion: methylation, oxidation, phosphorylation, and acetylation.

• 

  Fig. 2 Secretion mechanism and inflammatory role of HMGB1 in redox states. (A) HMGB1 is translocated to the extracellular environment via two secretion mechanisms: active secretion by inflammatory cells or passive release by necrotic or apoptotic cells. HMGB1 in the nucleus is actively secreted when immunologically competent cells are activated by inflammatory stimulus and undergo post-translation modifications such as acetylation, phosphorylation, methylation, and redox change. Passive release of HMGB1 is mediated by necrotic or apoptotic cell death caused by injury. Released HMGB1 triggers inflammatory responses in the body. (B) The inflammatory activity of released extracellular HMGB1 is dependent upon its redox state. HMGB1 consists of three cysteine residues (C23, C45, C106) that are modified during redox change. The reduced form of HMGB1 with all thiol groups defines the chemokine activity of HMGB1, whereas the disulfide-HMGB1 with C23 and C45, forming an intermolecular disulfide bond, induces cytokine activity. The fully oxidized form of HMGB1 has no known immune function in the cells.

• 

  Fig. 3 HMGB1 binding to receptors and activating signal transduction pathway. Interaction of HMGB1 with RAGE, TLR2, TLR4, and TLR9 transduce cellular signals through a common pathway that leads to activation of NF-κB. HMGB1 interaction with LPS, LTA, and CpG enhances TLR4-, TLR2-, and TLR9-mediated signaling, respectively, and further leads to downstream signaling of NF-κB activation and proinflammatory cytokine production. Activated NF-κB gets released from IκB translocates to the nucleus and binds to the DNA in the most abundant form of NF-κB, the p65/p50 heterodimer form. HMGB1 also interacts with CXCL12, which binds to CXCR4 and induces chemotaxis and recruitment of inflammatory cells.

• 

  Fig. 4 Targeting HMGB1 as a potential therapeutic approach for inflammatory diseases. HMGB1 can be targeted in various areas to potentially block the proinflammatory cytokine effect of HMGB1 in inflammatory disease models. HMGB1 is actively released upon infection by inflammatory cells or passively released by necrotic cells. Inhibiting the release of HMGB1 and blocking the activity of extracellular HMGB1 can reduce the inflammatory responses induced by HMGB1. Blockade of HMGB1 binding receptors can inhibit the production of proinflammatory cytokines by HMGB1 in immune cells.

Reference

1. Goodwin GH, Rabbani A, Nicolas PH, Johns EW. The isolation of the high mobility group non-histone chromosomal protein HMG 14. FEBS Lett. 1977; 80:413–416.

2. Goodwin GH, Sanders C, Johns EW. A new group of chromatin-associated proteins with a high content of acidic and basic amino acids. Eur J Biochem. 1973; 38:14–19.

3. Javaherian K, Liu JF, Wang JC. Nonhistone proteins HMG1 and HMG2 change the DNA helical structure. Science. 1978; 199:1345–1346.

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

5. Min HJ, Ko EA, Wu J, Kim ES, Kwon MK, Kwak MS, et al. Chaperone-like activity of high-mobility group box 1 protein and its role in reducing the formation of polyglutamine aggregates. J Immunol. 2013; 190:1797–1806.

6. Bianchi ME, Beltrame M, Paonessa G. Specific recognition of cruciform DNA by nuclear protein HMG1. Science. 1989; 243(4894 Pt 1):1056–1059.

7. Giese K, Cox J, Grosschedl R. The HMG domain of lymphoid enhancer factor 1 bends DNA and facilitates assembly of functional nucleoprotein structures. Cell. 1992; 69:185–195.

8. Tang D, Kang R, Livesey KM, Cheh CW, Farkas A, Loughran P, et al. Endogenous HMGB1 regulates autophagy. J Cell Biol. 2010; 190:881–892.

9. Wang H, Bloom O, Zhang M, Vishnubhakat JM, Ombrellino M, Che J, et al. HMG-1 as a late mediator of endotoxin lethality in mice. Science. 1999; 285:248–251.

10. Calogero S, Grassi F, Aguzzi A, Voigtländer T, Ferrier P, Ferrari S, et al. The lack of chromosomal protein Hmg1 does not disrupt cell growth but causes lethal hypoglycaemia in newborn mice. Nat Genet. 1999; 22:276–280.

11. Taniguchi N, Yoshida K, Ito T, Tsuda M, Mishima Y, Furumatsu T, et al. Stage-specific secretion of HMGB1 in cartilage regulates endochondral ossification. Mol Cell Biol. 2007; 27:5650–5663.

12. Yanai H, Matsuda A, An J, Koshiba R, Nishio J, Negishi H, et al. Conditional ablation of HMGB1 in mice reveals its protective function against endotoxemia and bacterial infection. Proc Natl Acad Sci U S A. 2013; 110:20699–20704.

13. Bustin M. Revised nomenclature for high mobility group (HMG) chromosomal proteins. Trends Biochem Sci. 2001; 26:152–153.

14. Laudet V, Stehelin D, Clevers H. Ancestry and diversity of the HMG box superfamily. Nucleic Acids Res. 1993; 21:2493–2501.

15. Weir HM, Kraulis PJ, Hill CS, Raine AR, Laue ED, Thomas JO. Structure of the HMG box motif in the B-domain of HMG1. EMBO J. 1993; 12:1311–1319.

16. Yang H, Ochani M, Li J, Qiang X, Tanovic M, Harris HE, et al. Reversing established sepsis with antagonists of endogenous high-mobility group box 1. Proc Natl Acad Sci U S A. 2004; 101:296–301.

17. Ito T, Kawahara K, Okamoto K, Yamada S, Yasuda M, Imaizumi H, et al. Proteolytic cleavage of high mobility group box 1 protein by thrombin-thrombomodulin complexes. Arterioscler Thromb Vasc Biol. 2008; 28:1825–1830.

18. Li J, Kokkola R, Tabibzadeh S, Yang R, Ochani M, Qiang X, et al. Structural basis for the proinflammatory cytokine activity of high mobility group box 1. Mol Med. 2003; 9:37–45.

19. Yang H, Hreggvidsdottir HS, Palmblad K, Wang H, Ochani M, Li J, et al. A critical cysteine is required for HMGB1 binding to Toll-like receptor 4 and activation of macrophage cytokine release. Proc Natl Acad Sci U S A. 2010; 107:11942–11947.

20. Hori O, Brett J, Slattery T, Cao R, Zhang J, Chen JX, et al. The receptor for advanced glycation end products (RAGE) is a cellular binding site for amphoterin. Mediation of neurite outgrowth and co-expression of rage and amphoterin in the developing nervous system. J Biol Chem. 1995; 270:25752–25761.

21. Sparatore B, Passalacqua M, Patrone M, Melloni E, Pontremoli S. Extracellular high-mobility group 1 protein is essential for murine erythroleukaemia cell differentiation. Biochem J. 1996; 320(Pt 1):253–256.

22. Mitkova E, Ugrinova I, Pashev IG, Pasheva EA. The inhibitory effect of HMGB-1 protein on the repair of cisplatin-damaged DNA is accomplished through the acidic domain. Biochemistry. 2005; 44:5893–5898.

23. Belgrano FS, de Abreu da Silva IC, Bastos de Oliveira FM, Fantappié MR, Mohana-Borges R. Role of the acidic tail of high mobility group protein B1 (HMGB1) in protein stability and DNA bending. PLoS One. 2013; 8:e79572.

24. Knapp S, Müller S, Digilio G, Bonaldi T, Bianchi ME, Musco G. 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. 2004; 43:11992–11997.

25. Watson M, Stott K, Thomas JO. Mapping intramolecular interactions between domains in HMGB1 using a tail-truncation approach. J Mol Biol. 2007; 374:1286–1297.

26. Youn JH, Kwak MS, Wu J, Kim ES, Ji Y, Min HJ, et al. Identification of lipopolysaccharide-binding peptide regions within HMGB1 and their effects on subclinical endotoxemia in a mouse model. Eur J Immunol. 2011; 41:2753–2762.

27. Bonaldi T, Talamo F, Scaffidi P, Ferrera D, Porto A, Bachi A, et al. Monocytic cells hyperacetylate chromatin protein HMGB1 to redirect it towards secretion. EMBO J. 2003; 22:5551–5560.

28. Hoppe G, Talcott KE, Bhattacharya SK, Crabb JW, Sears JE. Molecular basis for the redox control of nuclear transport of the structural chromatin protein Hmgb1. Exp Cell Res. 2006; 312:3526–3538.

29. Youn JH, Shin JS. Nucleocytoplasmic shuttling of HMGB1 is regulated by phosphorylation that redirects it toward secretion. J Immunol. 2006; 177:7889–7897.

30. Ito I, Fukazawa J, Yoshida M. Post-translational methylation of high mobility group box 1 (HMGB1) causes its cytoplasmic localization in neutrophils. J Biol Chem. 2007; 282:16336–16344.

31. Andersson U, Wang H, Palmblad K, Aveberger AC, Bloom O, Erlandsson-Harris H, et al. High mobility group 1 protein (HMG-1) stimulates proinflammatory cytokine synthesis in human monocytes. J Exp Med. 2000; 192:565–570.

32. Gardella S, Andrei C, Ferrera D, Lotti LV, Torrisi MR, Bianchi ME, et al. The nuclear protein HMGB1 is secreted by monocytes via a non-classical, vesicle-mediated secretory pathway. EMBO Rep. 2002; 3:995–1001.

33. Oh YJ, Youn JH, Ji Y, Lee SE, Lim KJ, Choi JE, et al. HMGB1 is phosphorylated by classical protein kinase C and is secreted by a calcium-dependent mechanism. J Immunol. 2009; 182:5800–5809.

34. Oh YJ, Youn JH, Min HJ, Kim DH, Lee SS, Choi IH, et al. CKD712, (S)-1-(α-naphthylmethyl)-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline, inhibits the lipopolysaccharide-stimulated secretion of HMGB1 by inhibiting PI3K and classical protein kinase C. Int Immunopharmacol. 2011; 11:1160–1165.

35. Venereau E, Casalgrandi M, Schiraldi M, Antoine DJ, Cattaneo A, De Marchis F, et al. Mutually exclusive redox forms of HMGB1 promote cell recruitment or proinflammatory cytokine release. J Exp Med. 2012; 209:1519–1528.

36. Tang D, Billiar TR, Lotze MT. A Janus tale of two active high mobility group box 1 (HMGB1) redox states. Mol Med. 2012; 18:1360–1362.

37. Tang D, Kang R, Cheh CW, Livesey KM, Liang X, Schapiro NE, et al. HMGB1 release and redox regulates autophagy and apoptosis in cancer cells. Oncogene. 2010; 29:5299–5310.

38. Falciola L, Spada F, Calogero S, Langst G, Voit R, Grummt I, et al. High mobility group 1 protein is not stably associated with the chromosomes of somatic cells. J Cell Biol. 1997; 137:19–26.

39. Scaffidi P, Misteli T, Bianchi ME. Release of chromatin protein HMGB1 by necrotic cells triggers inflammation. Nature. 2002; 418:191–195.

40. Rovere-Querini P, Capobianco A, Scaffidi P, Valentinis B, Catalanotti F, Giazzon M, et al. HMGB1 is an endogenous immune adjuvant released by necrotic cells. EMBO Rep. 2004; 5:825–830.

41. Bell CW, Jiang W, Reich CF 3rd, Pisetsky DS. The extracellular release of HMGB1 during apoptotic cell death. Am J Physiol Cell Physiol. 2006; 291:C1318–C1325.

42. Qin S, Wang H, Yuan R, Li H, Ochani M, Ochani K, et al. Role of HMGB1 in apoptosis-mediated sepsis lethality. J Exp Med. 2006; 203:1637–1642.

43. Paull TT, Haykinson MJ, Johnson RC. The nonspecific DNA-binding and -bending proteins HMG1 and HMG2 promote the assembly of complex nucleoprotein structures. Genes Dev. 1993; 7:1521–1534.

44. Sha Y, Zmijewski J, Xu Z, Abraham E. HMGB1 develops enhanced proinflammatory activity by binding to cytokines. J Immunol. 2008; 180:2531–2537.

45. Urbonaviciute V, Fürnrohr BG, Meister S, Munoz L, Heyder P, De Marchis F, et al. Induction of inflammatory and immune responses by HMGB1-nucleosome complexes: implications for the pathogenesis of SLE. J Exp Med. 2008; 205:3007–3018.

46. Youn JH, Oh YJ, Kim ES, Choi JE, Shin JS. High mobility group box 1 protein binding to lipopolysaccharide facilitates transfer of lipopolysaccharide to CD14 and enhances lipopolysaccharide-mediated TNF-alpha production in human monocytes. J Immunol. 2008; 180:5067–5074.

47. Campana L, Bosurgi L, Bianchi ME, Manfredi AA, Rovere-Querini P. Requirement of HMGB1 for stromal cell-derived factor-1/CXCL12-dependent migration of macrophages and dendritic cells. J Leukoc Biol. 2009; 86:609–615.

48. Tian J, Avalos AM, Mao SY, Chen B, Senthil K, Wu H, et al. Toll-like receptor 9-dependent activation by DNA-containing immune complexes is mediated by HMGB1 and RAGE. Nat Immunol. 2007; 8:487–496.

49. Dumitriu IE, Baruah P, Valentinis B, Voll RE, Herrmann M, Nawroth PP, et al. Release of high mobility group box 1 by dendritic cells controls T cell activation via the receptor for advanced glycation end products. J Immunol. 2005; 174:7506–7515.

50. Huttunen HJ, Fages C, Rauvala H. Receptor for advanced glycation end products (RAGE)-mediated neurite outgrowth and activation of NF-kappaB require the cytoplasmic domain of the receptor but different downstream signaling pathways. J Biol Chem. 1999; 274:19919–19924.

51. Park JS, Arcaroli J, Yum HK, Yang H, Wang H, Yang KY, et al. Activation of gene expression in human neutrophils by high mobility group box 1 protein. Am J Physiol Cell Physiol. 2003; 284:C870–C879.

52. Taguchi A, Blood DC, del Toro G, Canet A, Lee DC, Qu W, et al. Blockade of RAGE-amphoterin signalling suppresses tumour growth and metastases. Nature. 2000; 405:354–360.

53. Park BS, Song DH, Kim HM, Choi BS, Lee H, Lee JO. The structural basis of lipopolysaccharide recognition by the TLR4-MD-2 complex. Nature. 2009; 458:1191–1195.

54. Kim S, Kim SY, Pribis JP, Lotze M, Mollen KP, Shapiro R, et al. Signaling of high mobility group box 1 (HMGB1) through toll-like receptor 4 in macrophages requires CD14. Mol Med. 2013; 19:88–98.

55. Schröder NW, Morath S, Alexander C, Hamann L, Hartung T, Zähringer U, et al. Lipoteichoic acid (LTA) of Streptococcus pneumoniae and Staphylococcus aureus activates immune cells via Toll-like receptor (TLR)-2, lipopolysaccharide-binding protein (LBP), and CD14, whereas TLR-4 and MD-2 are not involved. J Biol Chem. 2003; 278:15587–15594.

56. Latz E, Schoenemeyer A, Visintin A, Fitzgerald KA, Monks BG, Knetter CF, et al. TLR9 signals after translocating from the ER to CpG DNA in the lysosome. Nat Immunol. 2004; 5:190–198.

57. Ivanov S, Dragoi AM, Wang X, Dallacosta C, Louten J, Musco G, et al. A novel role for HMGB1 in TLR9-mediated inflammatory responses to CpG-DNA. Blood. 2007; 110:1970–1981.

58. Teicher BA, Fricker SP. CXCL12 (SDF-1)/CXCR4 pathway in cancer. Clin Cancer Res. 2010; 16:2927–2931.

59. Schiraldi M, Raucci A, Muñoz LM, Livoti E, Celona B, Venereau E, et al. HMGB1 promotes recruitment of inflammatory cells to damaged tissues by forming a complex with CXCL12 and signaling via CXCR4. J Exp Med. 2012; 209:551–563.

60. Kazama H, Ricci JE, Herndon JM, Hoppe G, Green DR, Ferguson TA. Induction of immunological tolerance by apoptotic cells requires caspase-dependent oxidation of high-mobility group box-1 protein. Immunity. 2008; 29:21–32.

61. Antoine DJ, Williams DP, Kipar A, Laverty H, Park BK. Diet restriction inhibits apoptosis and HMGB1 oxidation and promotes inflammatory cell recruitment during acetaminophen hepatotoxicity. Mol Med. 2010; 16:479–490.

62. Yang H, Lundbäck P, Ottosson L, Erlandsson-Harris H, Venereau E, Bianchi ME, et al. Redox modification of cysteine residues regulates the cytokine activity of high mobility group box-1 (HMGB1). Mol Med. 2012; 18:250–259.

63. Saitoh S, Akashi S, Yamada T, Tanimura N, Matsumoto F, Fukase K, et al. Ligand-dependent Toll-like receptor 4 (TLR4)-oligomerization is directly linked with TLR4-signaling. J Endotoxin Res. 2004; 10:257–260.

64. Oppenheim JJ, Yang D. Alarmins: chemotactic activators of immune responses. Curr Opin Immunol. 2005; 17:359–365.

65. Yang D, Oppenheim JJ. Antimicrobial proteins act as "alarmins" in joint immune defense. Arthritis Rheum. 2004; 50:3401–3403.

66. Ganz T. Defensins: antimicrobial peptides of innate immunity. Nat Rev Immunol. 2003; 3:710–720.

67. Yang D, Chen Q, Yang H, Tracey KJ, Bustin M, Oppenheim JJ. High mobility group box-1 protein induces the migration and activation of human dendritic cells and acts as an alarmin. J Leukoc Biol. 2007; 81:59–66.

68. 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. 2005; 106:609–616.

69. Messmer D, Yang H, Telusma G, Knoll F, Li J, Messmer B, et al. High mobility group box protein 1: an endogenous signal for dendritic cell maturation and Th1 polarization. J Immunol. 2004; 173:307–313.

70. Srikrishna G, Huttunen HJ, Johansson L, Weigle B, Yamaguchi Y, Rauvala H, et al. N -Glycans on the receptor for advanced glycation end products influence amphoterin binding and neurite outgrowth. J Neurochem. 2002; 80:998–1008.

71. Chen GY, Nuñez G. Sterile inflammation: sensing and reacting to damage. Nat Rev Immunol. 2010; 10:826–837.

72. Mbitikon-Kobo FM, Vocanson M, Michallet MC, Tomkowiak M, Cottalorda A, Angelov GS, et al. Characterization of a CD44/CD122int memory CD8 T cell subset generated under sterile inflammatory conditions. J Immunol. 2009; 182:3846–3854.

73. Kokkola R, Andersson A, Mullins G, Ostberg T, Treutiger CJ, Arnold B, et al. RAGE is the major receptor for the proinflammatory activity of HMGB1 in rodent macrophages. Scand J Immunol. 2005; 61:1–9.

74. Goldstein RS, Gallowitsch-Puerta M, Yang L, Rosas-Ballina M, Huston JM, Czura CJ, et al. Elevated high-mobility group box 1 levels in patients with cerebral and myocardial ischemia. Shock. 2006; 25:571–574.

75. Levy RM, Mollen KP, Prince JM, Kaczorowski DJ, Vallabhaneni R, Liu S, et al. Systemic inflammation and remote organ injury following trauma require HMGB1. Am J Physiol Regul Integr Comp Physiol. 2007; 293:R1538–R1544.

76. Taniguchi N, Kawahara K, Yone K, Hashiguchi T, Yamakuchi M, Goto M, et al. High mobility group box chromosomal protein 1 plays a role in the pathogenesis of rheumatoid arthritis as a novel cytokine. Arthritis Rheum. 2003; 48:971–981.

77. Popovic K, Ek M, Espinosa A, Padyukov L, Harris HE, Wahren-Herlenius M, et al. Increased expression of the novel proinflammatory cytokine high mobility group box chromosomal protein 1 in skin lesions of patients with lupus erythematosus. Arthritis Rheum. 2005; 52:3639–3645.

78. Straino S, Di Carlo A, Mangoni A, De Mori R, Guerra L, Maurelli R, et al. High-mobility group box 1 protein in human and murine skin: involvement in wound healing. J Invest Dermatol. 2008; 128:1545–1553.

79. Mitola S, Belleri M, Urbinati C, Coltrini D, Sparatore B, Pedrazzi M, et al. Cutting edge: extracellular high mobility group box-1 protein is a proangiogenic cytokine. J Immunol. 2006; 176:12–15.

80. Kang R, Livesey KM, Zeh HJ, Loze MT, Tang D. HMGB1: a novel Beclin 1-binding protein active in autophagy. Autophagy. 2010; 6:1209–1211.

81. Kang R, Livesey KM, Zeh HJ 3rd, Lotze MT, Tang D. Metabolic regulation by HMGB1-mediated autophagy and mitophagy. Autophagy. 2011; 7:1256–1258.

82. Huebener P, Gwak GY, Pradere JP, Quinzii CM, Friedman R, Lin CS, et al. High-mobility group box 1 is dispensable for autophagy, mitochondrial quality control, and organ function in vivo. Cell Metab. 2014; 19:539–547.

83. Conti L, Lanzardo S, Arigoni M, Antonazzo R, Radaelli E, Cantarella D, et al. The noninflammatory role of high mobility group box 1/Toll-like receptor 2 axis in the self-renewal of mammary cancer stem cells. FASEB J. 2013; 27:4731–4744.

84. Tye H, Kennedy CL, Najdovska M, McLeod L, McCormack W, Hughes N, et al. STAT3-driven upregulation of TLR2 promotes gastric tumorigenesis independent of tumor inflammation. Cancer Cell. 2012; 22:466–478.

85. Korkaya H, Liu S, Wicha MS. Regulation of cancer stem cells by cytokine networks: attacking cancer's inflammatory roots. Clin Cancer Res. 2011; 17:6125–6129.

86. Liu Z, Bandyopadhyay A, Nichols RW, Wang L, Hinck AP, Wang S, et al. Blockade of Autocrine TGF-β Signaling Inhibits Stem Cell Phenotype, Survival, and Metastasis of Murine Breast Cancer Cells. J Stem Cell Res Ther. 2012; 2:1–8.

87. Schlueter C, Weber H, Meyer B, Rogalla P, Röser K, Hauke S, et al. Angiogenetic signaling through hypoxia: HMGB1: an angiogenetic switch molecule. Am J Pathol. 2005; 166:1259–1263.

88. Lin Q, Yang XP, Fang D, Ren X, Zhou H, Fang J, et al. High-mobility group box-1 mediates toll-like receptor 4-dependent angiogenesis. Arterioscler Thromb Vasc Biol. 2011; 31:1024–1032.

89. van Beijnum JR, Nowak-Sliwinska P, van den Boezem E, Hautvast P, Buurman WA, Griffioen AW. Tumor angiogenesis is enforced by autocrine regulation of high-mobility group box 1. Oncogene. 2013; 32:363–374.

90. Aneja RK, Tsung A, Sjodin H, Gefter JV, Delude RL, Billiar TR, et al. Preconditioning with high mobility group box 1 (HMGB1) induces lipopolysaccharide (LPS) tolerance. J Leukoc Biol. 2008; 84:1326–1334.

91. Robert SM, Sjodin H, Fink MP, Aneja RK. Preconditioning with high mobility group box 1 (HMGB1) induces lipoteichoic acid (LTA) tolerance. J Immunother. 2010; 33:663–671.

92. Choi J, Min HJ, Shin JS. Increased levels of HMGB1 and pro-inflammatory cytokines in children with febrile seizures. J Neuroinflammation. 2011; 8:135.

93. Kissoon N, Carcillo JA, Espinosa V, Argent A, Devictor D, Madden M, et al. World Federation of Pediatric Intensive Care and Critical Care Societies: Global Sepsis Initiative. Pediatr Crit Care Med. 2011; 12:494–503.

94. Li W, Ashok M, Li J, Yang H, Sama AE, Wang H. A major ingredient of green tea rescues mice from lethal sepsis partly by inhibiting HMGB1. PLoS One. 2007; 2:e1153.

95. Ellerman JE, Brown CK, de Vera M, Zeh HJ, Billiar T, Rubartelli A, et al. Masquerader: high mobility group box-1 and cancer. Clin Cancer Res. 2007; 13:2836–2848.

96. Brezniceanu ML, Völp K, Bösser S, Solbach C, Lichter P, Joos S, et al. HMGB1 inhibits cell death in yeast and mammalian cells and is abundantly expressed in human breast carcinoma. FASEB J. 2003; 17:1295–1297.

97. Poser I, Golob M, Buettner R, Bosserhoff AK. Upregulation of HMG1 leads to melanoma inhibitory activity expression in malignant melanoma cells and contributes to their malignancy phenotype. Mol Cell Biol. 2003; 23:2991–2998.

98. Bassi R, Giussani P, Anelli V, Colleoni T, Pedrazzi M, Patrone M, et al. HMGB1 as an autocrine stimulus in human T98G glioblastoma cells: role in cell growth and migration. J Neurooncol. 2008; 87:23–33.

99. Dong Xda E, Ito N, Lotze MT, Demarco RA, Popovic P, Shand SH, et al. High mobility group box I (HMGB1) release from tumor cells after treatment: implications for development of targeted chemoimmunotherapy. J Immunother. 2007; 30:596–606.