, Volume 11, Issue 1, pp 91–99 | Cite as

Convergence and amplification of toll-like receptor (TLR) and receptor for advanced glycation end products (RAGE) signaling pathways via high mobility group B1 (HMGB1)

  • Judy R. van BeijnumEmail author
  • Wim A. Buurman
  • Arjan W. Griffioen
Original Paper


Sustained proinflammatory responses in rheumatoid arthritis, atherosclerosis, and diabetic retinopathy, as well as in cancer, are often associated with increased angiogenesis that contributes to tissue disruption and disease progression. High mobility group B1 (HMGB1) has been recognized as a proinflammatory cytokine and more recently, as a proangiogenic factor. HMGB1 can either be passively released from necrotic cells or actively secreted in response to angiogenic and inflammatory signals. HMGB1 itself may signal through the receptor for advanced glycation end products (RAGE), and via toll-like receptors, TLR2 and TLR4. Activation of these receptors results in the activation of NFκB, which induces the upregulation of leukocyte adhesion molecules and the production of proinflammatory cytokines and angiogenic factors in both hematopoietic and endothelial cells, thereby promoting inflammation. Interestingly, HMGB1 seems to be involved in a positive feedback mechanism, that may help to sustain inflammation and angiogenesis in several pathological conditions, thereby contributing to disease progression. Endothelial cells express HMGB1, as well as the receptors RAGE, TLR2, and TLR4, and in diverse pathologies HMGB1 and its receptors are overexpressed. Furthermore, HMGB1-induced signaling can activate NFκB, which can subsequently induce the expression of HMGB1 receptors. Thus, HMGB1 can mediate amplification of inflammation and angiogenesis through increased secretion of HMGB1 and increased expression of the receptors it can interact with. In this review, we discuss signaling cascades that HMGB1 can induce via TLRs and RAGE, as well as its contribution to pathologies involving endothelial cells.


HMGB1 Angiogenesis RAGE TLR 



Endothelial cell


High mobility group B1


Receptor for advanced glycation end products


Toll-like receptor


Nuclear factor κ B


Vascular endothelial growth factor




Tumor necrosis factor α




  1. 1.
    van Beijnum JR, Griffioen AW (2005) In silico analysis of angiogenesis associated gene expression identifies angiogenic stage related profiles. Biochim Biophys Acta 1755:121–134PubMedGoogle Scholar
  2. 2.
    van Beijnum JR, Dings RP, van der Linden E et al (2006) Gene expression of tumor angiogenesis dissected: specific targeting of colon cancer angiogenic vasculature. Blood 108:2339–2348PubMedCrossRefGoogle Scholar
  3. 3.
    Javaherian K, Liu JF, Wang JC (1978) Nonhistone proteins HMG1 and HMG2 change the DNA helical structure. Science 199:1345–1346PubMedCrossRefGoogle Scholar
  4. 4.
    Rauvala H, Pihlaskari R (1987) Isolation and some characteristics of an adhesive factor of brain that enhances neurite outgrowth in central neurons. J Biol Chem 262:16625–16635PubMedGoogle Scholar
  5. 5.
    Wang H, Bloom O, Zhang M et al (1999) HMG-1 as a late mediator of endotoxin lethality in mice. Science 285:248–251PubMedCrossRefGoogle Scholar
  6. 6.
    Andersson U, Wang H, Palmblad K et al (2000) High mobility group 1 protein (HMG-1) stimulates proinflammatory cytokine synthesis in human monocytes. J Exp Med 192:565–570PubMedCrossRefGoogle Scholar
  7. 7.
    Fiuza C, Bustin M, Talwar S et al (2003) Inflammation-promoting activity of HMGB1 on human microvascular endothelial cells. Blood 101:2652–2660PubMedCrossRefGoogle Scholar
  8. 8.
    Mitola S, Belleri M, Urbinati C et al (2006) Cutting edge: extracellular high mobility group box-1 protein is a proangiogenic cytokine. J Immunol 176:12–15PubMedGoogle Scholar
  9. 9.
    Schlueter C, Weber H, Meyer B et al (2005) Angiogenetic signaling through hypoxia: HMGB1: an angiogenetic switch molecule. Am J Pathol 166:1259–1263PubMedGoogle Scholar
  10. 10.
    Huttunen HJ, Rauvala H (2004) Amphoterin as an extracellular regulator of cell motility: from discovery to disease. J Intern Med 255:351–366PubMedCrossRefGoogle Scholar
  11. 11.
    Bianchi ME, Beltrame M, Paonessa G (1989) Specific recognition of cruciform DNA by nuclear protein HMG1. Science 243:1056–1059PubMedCrossRefGoogle Scholar
  12. 12.
    Lotze MT, Tracey KJ (2005) High-mobility group box 1 protein (HMGB1): nuclear weapon in the immune arsenal. Nat Rev Immunol 5:331–342PubMedCrossRefGoogle Scholar
  13. 13.
    Stros M, Ozaki T, Bacikova A et al (2002) HMGB1 and HMGB2 cell-specifically down-regulate the p53- and p73-dependent sequence-specific transactivation from the human Bax gene promoter. J Biol Chem 277:7157–7164PubMedCrossRefGoogle Scholar
  14. 14.
    Merenmies J, Pihlaskari R, Laitinen J et al (1991) 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 266:16722–16729PubMedGoogle Scholar
  15. 15.
    Mullins GE, Sunden-Cullberg J, Johansson AS et al (2004) Activation of human umbilical vein endothelial cells leads to relocation and release of high-mobility group box chromosomal protein 1. Scand J Immunol 60:566–573PubMedCrossRefGoogle Scholar
  16. 16.
    Rouhiainen A, Kuja-Panula J, Wilkman E et al (2004) Regulation of monocyte migration by amphoterin (HMGB1). Blood 104:1174–1182PubMedCrossRefGoogle Scholar
  17. 17.
    Scaffidi P, Misteli T, Bianchi ME (2002) Release of chromatin protein HMGB1 by necrotic cells triggers inflammation. Nature 418:191–195PubMedCrossRefGoogle Scholar
  18. 18.
    Bonaldi T, Talamo F, Scaffidi P et al (2003) Monocytic cells hyperacetylate chromatin protein HMGB1 to redirect it towards secretion. EMBO J 22:5551–5560PubMedCrossRefGoogle Scholar
  19. 19.
    Semino C, Angelini G, Poggi A et al (2005) 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 106:609–616PubMedCrossRefGoogle Scholar
  20. 20.
    Ito I, Fukazawa J, Yoshida M (2007) Post-translational methylation of high mobility group box 1 (HMGB1) causes its cytoplasmic localization in neutrophils. J Biol Chem 282:16336–16344PubMedCrossRefGoogle Scholar
  21. 21.
    Youn JH, Shin JS (2006) Nucleocytoplasmic shuttling of HMGB1 is regulated by phosphorylation that redirects it toward secretion. J Immunol 177:7889–7897PubMedGoogle Scholar
  22. 22.
    Bianchi ME (2007) DAMPs, PAMPs and alarmins: all we need to know about danger. J Leukoc Biol 81:1–5PubMedCrossRefGoogle Scholar
  23. 23.
    Parkkinen J, Raulo E, Merenmies J et al (1993) Amphoterin, the 30-kDa protein in a family of HMG1-type polypeptides. Enhanced expression in transformed cells, leading edge localization, and interactions with plasminogen activation. J Biol Chem 268:19726–19738PubMedGoogle Scholar
  24. 24.
    Parkkinen J, Rauvala H (1991) Interactions of plasminogen and tissue plasminogen activator (t-PA) with amphoterin. Enhancement of t-PA-catalyzed plasminogen activation by amphoterin. J Biol Chem 266:16730–16735PubMedGoogle Scholar
  25. 25.
    Taguchi A, Blood DC, del Toro G et al (2000) Blockade of RAGE-amphoterin signalling suppresses tumour growth and metastases. Nature 405:354–360PubMedCrossRefGoogle Scholar
  26. 26.
    Treutiger CJ, Mullins GE, Johansson AS et al (2003) High mobility group 1 B-box mediates activation of human endothelium. J Intern Med 254:375–385PubMedCrossRefGoogle Scholar
  27. 27.
    Chavakis E, Hain A, Vinci M et al (2007) High-mobility group box 1 activates integrin-dependent homing of endothelial progenitor cells. Circ Res 100:204–212PubMedCrossRefGoogle Scholar
  28. 28.
    Palumbo R, Sampaolesi M, De Marchis F et al (2004) Extracellular HMGB1, a signal of tissue damage, induces mesoangioblast migration and proliferation. J Cell Biol 164:441–449PubMedCrossRefGoogle Scholar
  29. 29.
    Hori O, Brett J, Slattery T et al (1995) 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 270:25752–25761PubMedCrossRefGoogle Scholar
  30. 30.
    Yang H, Wang H, Czura CJ et al (2005) The cytokine activity of HMGB1. J Leukoc Biol 78:1–8PubMedCrossRefGoogle Scholar
  31. 31.
    Huttunen HJ, Fages C, Rauvala H (1999) 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 274:19919–19924PubMedCrossRefGoogle Scholar
  32. 32.
    Yan SD, Schmidt AM, Anderson GM et al (1994) Enhanced cellular oxidant stress by the interaction of advanced glycation end products with their receptors/binding proteins. J Biol Chem 269:9889–9897PubMedGoogle Scholar
  33. 33.
    Park JS, Arcaroli J, Yum HK et al (2003) Activation of gene expression in human neutrophils by high mobility group box 1 protein. Am J Physiol Cell Physiol 284:C870–C879PubMedGoogle Scholar
  34. 34.
    Park JS, Gamboni-Robertson F, He Q et al (2006) High mobility group box 1 protein interacts with multiple Toll-like receptors. Am J Physiol Cell Physiol 290:C917–C924PubMedCrossRefGoogle Scholar
  35. 35.
    Park JS, Svetkauskaite D, He Q et al (2004) Involvement of toll-like receptors 2 and 4 in cellular activation by high mobility group box 1 protein. J Biol Chem 279:7370–7377PubMedCrossRefGoogle Scholar
  36. 36.
    Yu M, Wang H, Ding A et al (2006) HMGB1 signals through toll-like receptor (TLR) 4 and TLR2. Shock 26:174–179PubMedCrossRefGoogle Scholar
  37. 37.
    Lentschat A, Karahashi H, Michelsen KS et al (2005) Mastoparan, a G protein agonist peptide, differentially modulates TLR4- and TLR2-mediated signaling in human endothelial cells and murine macrophages. J Immunol 174:4252–4261PubMedGoogle Scholar
  38. 38.
    Faure E, Equils O, Sieling PA et al (2000) Bacterial lipopolysaccharide activates NF-kappaB through toll-like receptor 4 (TLR-4) in cultured human dermal endothelial cells. Differential expression of TLR-4 and TLR-2 in endothelial cells. J Biol Chem 275:11058–11063PubMedCrossRefGoogle Scholar
  39. 39.
    Faure E, Thomas L, Xu H et al (2001) Bacterial lipopolysaccharide and IFN-gamma induce Toll-like receptor 2 and Toll-like receptor 4 expression in human endothelial cells: role of NF-kappa B activation. J Immunol 166:2018–2024PubMedGoogle Scholar
  40. 40.
    Arbibe L, Mira JP, Teusch N et al (2000) Toll-like receptor 2-mediated NF-kappa B activation requires a Rac1-dependent pathway. Nat Immunol 1:533–540PubMedCrossRefGoogle Scholar
  41. 41.
    Underhill DM, Ozinsky A, Smith KD et al (1999) Toll-like receptor-2 mediates mycobacteria-induced proinflammatory signaling in macrophages. Proc Natl Acad Sci USA 96:14459–14463PubMedCrossRefGoogle Scholar
  42. 42.
    Yang RB, Mark MR, Gurney AL et al (1999) Signaling events induced by lipopolysaccharide-activated toll-like receptor 2. J Immunol 163:639–643PubMedGoogle Scholar
  43. 43.
    Zhang FX, Kirschning CJ, Mancinelli R et al (1999) Bacterial lipopolysaccharide activates nuclear factor-kappaB through interleukin-1 signaling mediators in cultured human dermal endothelial cells and mononuclear phagocytes. J Biol Chem 274:7611–7614PubMedCrossRefGoogle Scholar
  44. 44.
    Akira S, Takeda K (2004) Toll-like receptor signalling. Nat Rev Immunol 4:499–511PubMedCrossRefGoogle Scholar
  45. 45.
    Kawai T, Akira S (2007) Signaling to NF-kappaB by Toll-like receptors. Trends Mol Med Google Scholar
  46. 46.
    Aomatsu K, Kato T, Fujita H et al (2008) Toll-like receptor agonists stimulate human neutrophil migration via activation of mitogen-activated protein kinases. Immunology 123:171–180PubMedGoogle Scholar
  47. 47.
    Koyasu S (2003) The role of PI3K in immune cells. Nat Immunol 4:313–319PubMedCrossRefGoogle Scholar
  48. 48.
    Ojaniemi M, Glumoff V, Harju K et al (2003) Phosphatidylinositol 3-kinase is involved in Toll-like receptor 4-mediated cytokine expression in mouse macrophages. Eur J Immunol 33:597–605PubMedCrossRefGoogle Scholar
  49. 49.
    Li X, Tupper JC, Bannerman DD et al (2003) Phosphoinositide 3 kinase mediates Toll-like receptor 4-induced activation of NF-kappa B in endothelial cells. Infect Immun 71:4414–4420PubMedCrossRefGoogle Scholar
  50. 50.
    Karin M, Ben-Neriah Y (2000) Phosphorylation meets ubiquitination: the control of NF-[kappa]B activity. Annu Rev Immunol 18:621–663PubMedCrossRefGoogle Scholar
  51. 51.
    Kuniyasu H, Chihara Y, Takahashi T (2003) Co-expression of receptor for advanced glycation end products and the ligand amphoterin associates closely with metastasis of colorectal cancer. Oncol Rep 10:445–448PubMedGoogle Scholar
  52. 52.
    Sasahira T, Akama Y, Fujii K et al (2005) Expression of receptor for advanced glycation end products and HMGB1/amphoterin in colorectal adenomas. Virchows Arch 446:411–415PubMedCrossRefGoogle Scholar
  53. 53.
    Kuniyasu H, Chihara Y, Kondo H et al (2003) Amphoterin induction in prostatic stromal cells by androgen deprivation is associated with metastatic prostate cancer. Oncol Rep 10:1863–1868PubMedGoogle Scholar
  54. 54.
    Sasahira T, Kirita T, Bhawal UK et al (2007) The expression of receptor for advanced glycation end products is associated with angiogenesis in human oral squamous cell carcinoma. Virchows Arch 450:287–295PubMedCrossRefGoogle Scholar
  55. 55.
    Yamagishi S, Yonekura H, Yamamoto Y et al (1997) Advanced glycation end products-driven angiogenesis in vitro. Induction of the growth and tube formation of human microvascular endothelial cells through autocrine vascular endothelial growth factor. J Biol Chem 272:8723–8730PubMedCrossRefGoogle Scholar
  56. 56.
    Zeh HJ III, Lotze MT (2005) Addicted to death: invasive cancer and the immune response to unscheduled cell death. J Immunother (1997) 28:1–9CrossRefGoogle Scholar
  57. 57.
    Bierhaus A, Humpert PM, Morcos M et al (2005) Understanding RAGE, the receptor for advanced glycation end products. J Mol Med 83:876–886PubMedCrossRefGoogle Scholar
  58. 58.
    Kim W, Hudson BI, Moser B et al (2005) Receptor for advanced glycation end products and its ligands: a journey from the complications of diabetes to its pathogenesis. Ann NY Acad Sci 1043:553–561PubMedCrossRefGoogle Scholar
  59. 59.
    Okamoto T, Yamagishi S, Inagaki Y et al (2002) Angiogenesis induced by advanced glycation end products and its prevention by cerivastatin. FASEB J 16:1928–1930PubMedGoogle Scholar
  60. 60.
    Pachydaki SI, Tari SR, Lee SE et al (2006) Upregulation of RAGE and its ligands in proliferative retinal disease. Exp Eye Res 82:807–815PubMedCrossRefGoogle Scholar
  61. 61.
    Firestein GS (1999) Starving the synovium: angiogenesis and inflammation in rheumatoid arthritis. J Clin Invest 103:3–4PubMedCrossRefGoogle Scholar
  62. 62.
    Cho ML, Ju JH, Kim HR et al (2007) Toll-like receptor 2 ligand mediates the upregulation of angiogenic factor, vascular endothelial growth factor and interleukin-8/CXCL8 in human rheumatoid synovial fibroblasts. Immunol Lett 108:121–128PubMedCrossRefGoogle Scholar
  63. 63.
    Kokkola R, Sundberg E, Ulfgren AK et al (2002) High mobility group box chromosomal protein 1: a novel proinflammatory mediator in synovitis. Arthritis Rheum 46:2598–2603PubMedCrossRefGoogle Scholar
  64. 64.
    Taniguchi N, Kawahara K, Yone K et al (2003) High mobility group box chromosomal protein 1 plays a role in the pathogenesis of rheumatoid arthritis as a novel cytokine. Arthritis Rheum 48:971–981PubMedCrossRefGoogle Scholar
  65. 65.
    Mullaly SC, Kubes P (2004) Toll gates and traffic arteries: from endothelial TLR2 to atherosclerosis. Circ Res 95:657–659PubMedCrossRefGoogle Scholar
  66. 66.
    Kalinina N, Agrotis A, Antropova Y et al (2004) Increased expression of the DNA-binding cytokine HMGB1 in human atherosclerotic lesions: role of activated macrophages and cytokines. Arterioscler Thromb Vasc Biol 24:2320–2325PubMedCrossRefGoogle Scholar
  67. 67.
    Erridge C, Spickett CM, Webb DJ (2007) Non-enterobacterial endotoxins stimulate human coronary artery but not venous endothelial cell activation via Toll-like receptor 2. Cardiovasc Res 73:181–189PubMedCrossRefGoogle Scholar
  68. 68.
    Edfeldt K, Swedenborg J, Hansson GK et al (2002) Expression of toll-like receptors in human atherosclerotic lesions: a possible pathway for plaque activation. Circulation 105:1158–1161PubMedGoogle Scholar
  69. 69.
    Harokopakis E, Albzreh MH, Martin MH et al (2006) TLR2 transmodulates monocyte adhesion and transmigration via Rac1- and PI3K-mediated inside-out signaling in response to Porphyromonas gingivalis fimbriae. J Immunol 176:7645–7656PubMedGoogle Scholar
  70. 70.
    Orlova VV, Choi EY, Xie C et al (2007) A novel pathway of HMGB1-mediated inflammatory cell recruitment that requires Mac-1-integrin. EMBO J 26:1129–1139PubMedCrossRefGoogle Scholar
  71. 71.
    Tabruyn SP, Griffioen AW (2007) A new role for NF-kappaB in angiogenesis inhibition. Cell Death Differ 14:1393–1397PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media B.V. 2008

Authors and Affiliations

  • Judy R. van Beijnum
    • 1
    Email author
  • Wim A. Buurman
    • 2
  • Arjan W. Griffioen
    • 1
  1. 1.Angiogenesis Laboratory, Department of Pathology, Research Institute for Growth and Development (GROW)Maastricht UniversityMaastrichtThe Netherlands
  2. 2.Department of General Surgery, Nutrition and Toxicology Research Institute Maastrich (NUTRIM)Maastricht UniversityMaastrichtThe Netherlands

Personalised recommendations