Cell Stress and Chaperones

, Volume 15, Issue 2, pp 123–141 | Cite as

Caught with their PAMPs down? The extracellular signalling actions of molecular chaperones are not due to microbial contaminants

  • Brian Henderson
  • Stuart K. Calderwood
  • Anthony R. M. Coates
  • Irun Cohen
  • Willem van Eden
  • Thomas Lehner
  • A. Graham Pockley
Mini Review


In recent years, it has been hypothesised that a new signalling system may exist in vertebrates in which secreted molecular chaperones form a dynamic continuum between the cellular stress response and corresponding homeostatic physiological mechanisms. This hypothesis seems to be supported by the finding that many molecular chaperones are released from cells and act as extracellular signals for a range of cells. However, this nascent field of biological research seems to suffer from an excessive criticism that the biological activities of molecular chaperones are due to undefined components of the microbial expression hosts used to generate recombinant versions of these proteins. In this article, a number of the proponents of the cell signalling actions of molecular chaperones take this criticism head-on. They show that sufficient evidence exists to support fully the hypothesis that molecular chaperones have cell–cell signalling actions that are likely to be part of the homeostatic mechanism of the vertebrate.


Heat shock proteins Endotoxin Innate immunity Adaptive immunity Inflammation Immunoregulation 



BH and ARMC wish to thank the Medical Research Council, Wellcome Trust, British Heart Foundation and Arthritis Research Campaign for funding their studies.


  1. Anderton SM, van der Zee R, Prakken B, Noordzij A, van Eden W (1995) Activation of T cells recognizing self 60-kD heat shock protein can protect against experimental arthritis. J Exp Med 181:943–952PubMedCrossRefGoogle Scholar
  2. Arnold-Schild D, Hanau D, Spehner D, Schmid C, Rammensee H-G, de la Salle H, Schild H (1999) Receptor-mediated endocytosis of heat shock proteins by professional antigen-presenting cells. J Immunol 162:3757–3760PubMedGoogle Scholar
  3. Arnold-Schild D, Kleist C, Welschof M, Opelz G, Rammensee HG, Schild H, Terness P (2000) One-step single-chain Fv recombinant antibody-based purification of gp96 for vaccine development. Cancer Res 60:4175–4178PubMedGoogle Scholar
  4. Asea A, Kraeft S-K, Kurt-Jones EA, Stevenson MA, Chen LB, Finberg RW, Koo GC, Calderwood SK (2000) Hsp70 stimulates cytokine production through a CD14-dependent pathway, demonstrating its dual role as a chaperone and cytokine. Nature Med 6:435–442PubMedCrossRefGoogle Scholar
  5. Asea A, Rehli M, Kabingu E, Boch JA, Baré O, Auron PE, Stevenson MA, Calderwood SK (2002) Novel signal transduction pathway utilized by extracellular HSP70. Role of Toll-like receptor (TLR) 2 and TLR4. J Biol Chem 277:15028–15034PubMedCrossRefGoogle Scholar
  6. Asquith KL, Baleato RM, McLaughlin EA, Nixon B, Aitken RJ (2004) Tyrosine phosphorylation activates surface chaperones facilitating sperm-zona recognition. J Cell Sci 117:3645–3657PubMedCrossRefGoogle Scholar
  7. Babaahmady K, Oehlmann W, Singh M, Lehner T (2007) Inhibition of human immunodeficiency virus type 1 infection of human CD4+ T cells by microbial HSP70 and the peptide epitope 407–426. J Virol 81:3354–3360PubMedCrossRefGoogle Scholar
  8. Baker-LePain JC, Sarzotti M, Fields TA, Li CY, Nicchitta CV (2002) GRP94 (gp96) and GRP94 N-terminal geldanamycin binding domain elicit tissue nonrestricted tumor suppression. J Exp Med 196:1447–1459PubMedCrossRefGoogle Scholar
  9. Baker-LePain JC, Sarzotti M, Nicchitta CV (2004) Glucose-regulated protein 94/glycoprotein 96 elicits bystander activation of CD4+ T cell Th1 cytokine production in vivo. J Immunol 172:4195–4203PubMedGoogle Scholar
  10. Bardwell JC, Craig EA (1984) Major heat shock gene of Drosophila and the Escherichia coli heatinducible dnaK gene are homologous. Proc Natl Acad Sci U S A 81:848–852PubMedCrossRefGoogle Scholar
  11. Basu S, Binder RJ, Suto R, Anderson KM, Srivastava PK (2000) Necrotic but not apoptotic cell death releases heat shock proteins, which deliver a partial maturation signal to dendritic cells and activates the NF-κB pathway. Int Immunol 12:1539–1546PubMedCrossRefGoogle Scholar
  12. Bendz H, Marincek BC, Momburg F, Ellwart JW, Issels RD, Nelson PJ, Noessner E (2008) Calcium signaling in dendritic cells by human or mycobacterial Hsp70 is caused by contamination and is not required for Hsp70-mediated enhancement of cross-presentation. J Biol Chem 283:26477–26483PubMedCrossRefGoogle Scholar
  13. Berwin B, Hart JP, Rice S, Gass C, Pizzo SV, Post SR, Nicchitta CV (2003) Scavenger receptor-A mediates gp96/GRP94 and calreticulin internalization by antigen-presenting cells. EMBO J 22:6127–6136PubMedCrossRefGoogle Scholar
  14. Berwin B, Delneste Y, Lovingood RV, Post SR, Pizzo SV (2004) SREC-I, a type F scavenger receptor, is an endocytic receptor for calreticulin. J Biol Chem 279:51250–51257PubMedCrossRefGoogle Scholar
  15. Binder RJ, Srivastava PK (2004) Essential role of CD91 in re-presentation of gp96-chaperoned peptides. Proc Natl Acad Sci USA 101:6128–6133PubMedCrossRefGoogle Scholar
  16. Binder RJ, Han DK, Srivastava PK (2000) CD91: a receptor for heat shock protein gp96. Nat Immunol 1:151–155PubMedCrossRefGoogle Scholar
  17. Bukau B, Horwich AL (1998) The Hsp70 and Hsp60 chaperone machines. Cell 92:351–366PubMedCrossRefGoogle Scholar
  18. Calderwood SK, Thériault J, Gray PJ, Gong J (2007) Cell surface receptors for molecular chaperones. Methods 43:199–206PubMedCrossRefGoogle Scholar
  19. Chandawarkar RY, Wagh MS, Srivastava PK (1999) The dual nature of specific immunological activity of tumor-derived gp96 preparations. J Exp Med 189:1437–1442PubMedCrossRefGoogle Scholar
  20. Chandawarkar RY, Wagh MS, Kovalchin JT, Srivastava P (2004) Immune modulation with high-dose heat-shock protein gp96: therapy of murine autoimmune diabetes and encephalomyelitis. Int Immunol 16:615–624PubMedCrossRefGoogle Scholar
  21. Cohen IR (2000) Tending Adam’s Garden: evolving the cognitive immune self. Academic Press, LondonGoogle Scholar
  22. Cohen IR, Holoshitz J, van Eden W, Frenkel A (1985) T lymphocyte clones illuminate pathogenesis and affect therapy of experimental arthritis. Arthritis Rheum 28:841–845PubMedCrossRefGoogle Scholar
  23. Cohen-Sfady M, Nussbaum G, Pevsner-Fischer M, Mor F, Carmi P, Zanin-Zhorov A, Lider O, Cohen IR (2005) Heat shock protein 60 activates B cells via the TLR4-MyD88 pathway. J Immunol 175:3594–3602PubMedGoogle Scholar
  24. Corrigall VM, Bodman-Smith MD, Fife MS, Canas B, Myers LK, Wooley P, Soh C, Staines NA, Pappin DJ, Berlo SE, van Eden W, van der Zee R, Lanchbury JS, Panayi GS (2001) The human endoplasmic reticulum molecular chaperone BiP is an autoantigen for rheumatoid arthritis and prevents the induction of experimental arthritis. J Immunol 166:1492–1498PubMedGoogle Scholar
  25. Corrigall VM, Bodman-Smith MD, Brunst M, Cornell H, Panayi GS (2004) Inhibition of antigen-presenting cell function and stimulation of human peripheral blood mononuclear cells to express an antiinflammatory cytokine profile by the stress protein BiP: relevance to the treatment of inflammatory arthritis. Arthritis Rheum 50:1164–1171PubMedCrossRefGoogle Scholar
  26. de Graeff-Meeder ER, van der Zee R, Rijkers GT, Schuurman HJ, Kuis W, Bijlsma JWJ, Zegers BJM, van Eden W (1991) Recognition of human 60 kD heat shock protein by mononuclear cells from patients with juvenile chronic arthritis. Lancet 337:1368–1372PubMedCrossRefGoogle Scholar
  27. de Graeff-Meeder ER, van Eden W, Rijkers GT, Prakken BJ, Kuis W, Voorhorst Ogink MM, van der Zee R, Schuurman HJ, Helders PJ, Zegers BJ (1995) Juvenile chronic arthritis: T-cell reactivity to human HSP60 in patients with a favorable course of arthritis. J Clin Invest 95:934–940PubMedCrossRefGoogle Scholar
  28. Delneste Y, Magistrelli G, Gauchat J, Haeuw J, Aubry J, Nakamura K, Kawakami-Honda N, Goetsch L, Sawamura T, Bonnefoy J, Jeannin P (2002) Involvement of LOX-1 in dendritic cell-mediated antigen cross-presentation. Immunity 17:353–362PubMedCrossRefGoogle Scholar
  29. Demine R, Walden P (2005) Testing the role of gp96 as peptide chaperone in antigen processing. J Biol Chem 280:17573–17578PubMedCrossRefGoogle Scholar
  30. Fairburn B, Muthana M, Hopkinson K, Slack LK, Mirza S, Georgiou AS, Espigares E, Wong C, Pockley AG (2006) Analysis of purified gp96 preparations from rat and mouse livers using 2-D gel electrophoresis and tandem mass spectrometry. Biochimie 88:1165–1174PubMedCrossRefGoogle Scholar
  31. Fearon WF, Fearon DT (2008) Inflammation and cardiovascular disease: role of the interleukin-1 receptor antagonist. Circulation 117:2577–2579PubMedCrossRefGoogle Scholar
  32. Figueiredo C, Wittmann M, Wang D, Dressel R, Seltsam A, Blasczyk R, Eiz-Vesper B (2009) Heat shock protein 70 (Hsp70) induces cytotoxicity of T-helper cells. Blood 113:3008–3016PubMedCrossRefGoogle Scholar
  33. Gao B, Tsan MF (2003a) Endotoxin contamination in recombinant human Hsp70 preparation is responsible for the induction of TNFα release by murine macrophages. J Biol Chem 278:174–179PubMedCrossRefGoogle Scholar
  34. Gao B, Tsan MF (2003b) Recombinant human heat shock protein 60 does not induce the release of tumor necrosis factor a from murine macrophages. J Biol Chem 278:22523–22529PubMedCrossRefGoogle Scholar
  35. Gao B, Tsan MF (2004) Induction of cytokines by heat shock proteins and endotoxin in murine macrophages. Biochem Biophys Res Commun 317:1149–1154PubMedCrossRefGoogle Scholar
  36. Gobert AP, Bambou JC, Werts C, Balloy V, Chignard M, Moran AP, Ferrero RL (2004) Helicobacter pylori heat shock protein 60 mediates interleukin-6 production by macrophages via a toll-like receptor (TLR)-2-, TLR-4-, and myeloid differentiation factor 88-independent mechanism. J Biol Chem 279:245–250PubMedCrossRefGoogle Scholar
  37. Habich C, Kempe K, Burkart V, Van Der Zee R, Lillicrap M, Gaston H, Kolb H (2004) Identification of the heat shock protein 60 epitope involved in receptor binding on macrophages. FEBS Lett 568:65–69PubMedCrossRefGoogle Scholar
  38. Henderson B, Henderson S (2009) Unfolding the relationship between secreted molecular chaperones and macrophage activation states. Cell Stress Chaperones 14:329–341PubMedCrossRefGoogle Scholar
  39. Henderson B, Pockley AG (2005) Molecular chaperones and cell signalling. Cambridge University Press, New YorkCrossRefGoogle Scholar
  40. Henderson B, Allan E, Coates AR (2006) Stress wars: the direct role of host and bacterial molecular chaperones in bacterial infection. Infect Immun 74:3693–3706PubMedCrossRefGoogle Scholar
  41. Hu Y, Henderson B, Lund PA, Tormay P, Ahmed MT, Gurcha SS, Besra GS, Coates AR (2008) A Mycobacterium tuberculosis mutant lacking the groEL homologue cpn60.1 is viable but fails to induce an inflammatory response in animal models of infection. Infect Immun 76:1535–1546PubMedCrossRefGoogle Scholar
  42. Hunt C, Morimoto RI (1985) Conserved features of eukaryotic hsp70 genes revealed by comparison with the nucleotide sequence of human hsp70. Proc Natl Acad Sci USA 82:6455–6459PubMedCrossRefGoogle Scholar
  43. Huurman VA, van der Meide PE, Duinkerken G, Willemen S, Cohen IR, Elias D, Roep BO (2008) Immunological efficacy of heat shock protein 60 peptide DiaPep277 therapy in clinical type I diabetes. Clin Exp Immunol 152:488–497PubMedGoogle Scholar
  44. Jeffery CJ (2003) Moonlighting proteins: old proteins learning new tricks. Trends Genet 19:415–417PubMedCrossRefGoogle Scholar
  45. Johnson BJ, Le TT, Dobbin CA, Banovic T, Howard CB, Flores de Mayo F, Vanags D, Naylor DJ, Hill GR, Suhrbier A (2005) Heat shock protein 10 inhibits lipopolysaccharide-induced inflammatory mediator production. J Biol Chem 280:4037–4047PubMedCrossRefGoogle Scholar
  46. Kamphuis S, Kuis W, de Jager W, Teklenburg G, Massa M, Gordon G, Boerhof M, Rijkers GT, Uiterwaal CS, Otten HG, Sette A, Albani S, Prakken BJ (2005) Tolerogenic immune responses to novel T-cell epitopes from heat-shock protein 60 in juvenile idiopathic arthritis. Lancet 366:50–56PubMedCrossRefGoogle Scholar
  47. Kampinga HH, Hageman J, Vos MJ, Kubota H, Tanguay RM, Bruford EA, Cheetham ME, Chen B, Hightower LE (2009) Guidelines for the nomenclature of the human heat shock proteins. Cell Stress Chaperones 14:105–111PubMedCrossRefGoogle Scholar
  48. Kim KP, Jagadeesan B, Burkholder KM, Jaradat ZW, Wampler JL, Lathrop AA, Morgan MT, Bhunia AK (2006) Adhesion characteristics of Listeria adhesion protein (LAP)-expressing Escherichia coli to Caco-2 cells and of recombinant LAP to eukaryotic receptor Hsp60 as examined in a surface plasmon resonance sensor. FEMS Microbiol Lett 256:324–332PubMedCrossRefGoogle Scholar
  49. Kirby AC, Meghji S, Nair SP, White P, Reddi K, Nishihara T, Nakashima K, Willis AC, Sim R, Wilson M, Henderson B (1995) The potent bone-resorbing mediator of Actinobacillus actinomycetemcomitans is homologous to the molecular chaperone GroEL. J Clin Invest 96:1185–1194PubMedCrossRefGoogle Scholar
  50. Kol A, Lichtman AH, Finberg RW, Libby P, Kurt-Jones EA (2000) Cutting edge: heat shock protein (HSP) 60 activates the innate immune response: CD14 is an essential receptor for HSP60 activation of mononuclear cells. J Immunol 164:13–17PubMedGoogle Scholar
  51. Kong TH, Coates ARM, Butcher PD, Hickman CJ, Shinnick TM (1993) Mycobacterium tuberculosis expresses two chaperonin-60 homologs. Proc Natl Acad Sci USA 90:2608–2612PubMedCrossRefGoogle Scholar
  52. Kovalchin JT, Mendonca C, Wagh MS, Wang R, Chandawarkar RY (2006) In vivo treatment of mice with heat shock protein, gp96, improves survival of skin grafts with minor and major antigenic disparity. Transplant Immunol 15:179–185CrossRefGoogle Scholar
  53. Lewthwaite JC, Coates ARM, Tormay P, Singh M, Mascagni P, Poole S, Roberts M, Sharp L, Henderson B (2001) Mycobacterium tuberculosis chaperonin 60.1 is a more potent cytokine stimulator than chaperonin 60.2 (hsp 65) and contains a CD14-binding domain. Infect Immun 69:7349–7355PubMedCrossRefGoogle Scholar
  54. Lewthwaite JC, George R, Lund PA, Poole S, Tormay P, Sharp L, Coates ARM, Henderson B (2002) Rhizobium leguminosarum chaperonin 60.3, but not chaperonin 60.1, induces cytokine production by human monocytes: activity is dependent on interaction with cell surface CD14. Cell Stress & Chaperones 7:130–136CrossRefGoogle Scholar
  55. Lindquist S, Craig EA (1988) The heat-shock proteins. Ann Rev Genetics 22:631–677CrossRefGoogle Scholar
  56. Liu B, Dai J, Zheng H, Stoilova D, Sun S, Li Z (2003) Cell surface expression of an endoplasmic reticulum resident heat shock protein gp96 triggers MyD88-dependent systemic autoimmune diseases. Proc Nat Acad Sci USA 100:15824–15829PubMedCrossRefGoogle Scholar
  57. Liu C, Ewing N, DeFilippo M (2004) Analytical challenges and strategies for the characterization of gp96-associated peptides. Methods 32:32–37PubMedCrossRefGoogle Scholar
  58. Mambula SS, Calderwood SK (2006) Heat shock protein 70 is secreted from tumor cells by a nonclassical pathway involving lysosomal endosomes. J Immunol 177:7849–7857PubMedGoogle Scholar
  59. Mambula SS, Stevenson MA, Ogawa K, Calderwood SK (2007) Mechanisms for Hsp70 secretion: crossing membranes without a leader. Methods 43:168–175PubMedCrossRefGoogle Scholar
  60. McLeish KR, Dean WL, Wellhausen SR, Stelzer GT (1989) Role of intracellular calcium in priming of human peripheral blood monocytes by bacterial lipopolysaccharide. Inflammation 13:681–692PubMedCrossRefGoogle Scholar
  61. Medzhitov R, Janeway C (2000) Innate immune recognition: mechanisms and pathways. Immunol Rev 173:89–97PubMedCrossRefGoogle Scholar
  62. Meghji S, White P, Nair SP, Reddi K, Heron K, Henderson B, Zaliani A, Fossati G, Mascagni P, Hunt JF, Roberts MM, Coates AR (1997) Mycobacterium tuberculosis chaperonin 10 stimulates bone resorption: a potential contributory factor in Pott's disease. J Exp Med 186:1241–1246PubMedCrossRefGoogle Scholar
  63. Meghji S, Lillicrap M, Maguire M, Tabona P, Gaston JSH, Poole S, Henderson B (2003) Human chaperonin 60 (Hsp60) stimulates bone resorption: Structure/function relationships. Bone 33:419–425PubMedCrossRefGoogle Scholar
  64. Mehlert A, Young DB (1989) Biochemical and antigenic characterization of the Mycobacterium tuberculosis 71kD antigen, a member of the 70kD heat-shock protein family. Mol Microbiol 3:125–130PubMedCrossRefGoogle Scholar
  65. Miller-Graziano CL, De A, Laudanski K, Herrmann T, Bandyopadhyay S (2008) HSP27: an anti-inflammatory and immunomodulatory stress protein acting to dampen immune function. Novartis Found Symp 291:196–208 discussion 208-111, 221-194PubMedCrossRefGoogle Scholar
  66. Mirza S, Muthana M, Fairburn B, Slack LK, Hopkinson K, Pockley AG (2006) The stress protein gp96 is not an activator of resting rat bone marrow-derived dendritic cells, but is a co-stimulator and activator of CD3+ T cells. Cell Stress Chaperones 11:364–378PubMedCrossRefGoogle Scholar
  67. Mitchell LA, Nixon B, Aitken RJ (2007) Analysis of chaperone proteins associated with human spermatozoa during capacitation. Mol Hum Reprod 13:605–613PubMedCrossRefGoogle Scholar
  68. Monks SA, Gaibor FP, Hassan-Zahraee M, Sawlivich W, Liu C, Rottman JB, Zabrecky JR (2005) The role of oligomeric structure in the biological activities of heat-shock protein, gp96. Immunology 114:148Google Scholar
  69. Morton H, Rolfe B, Clunie GJ (1977) An early pregnancy factor detected in human serum by the rosette inhibition test. Lancet 1:394–397PubMedCrossRefGoogle Scholar
  70. Nicchitta CV, Carrick DM, Baker-Lepain JC (2004) The messenger and the message: gp96 (GRP94)-peptide interactions in cellular immunity. Cell Stress Chaperones 9:325–331PubMedCrossRefGoogle Scholar
  71. Noonan FP, Halliday WJ, Morton H, Clunie GJ (1979) Early pregnancy factor is immunosuppressive. Nature 278:649–651PubMedCrossRefGoogle Scholar
  72. Novartis Foundation Symposium 291 (2008) The Biology of Extracellular Molecular Chaperones. Wiley, ChichesterGoogle Scholar
  73. Nussbaum G, Zanin-Zhorov A, Quintana F, Lider O, Cohen IR (2006) Peptide p277 of HSP60 signals T cells: inhibition of inflammatory chemotaxis. Int Immunol 18:1413–1419PubMedCrossRefGoogle Scholar
  74. Peetermans WE, Raats CJ, Langermans JA, van Furth R (1994) Mycobacterial heat-shock protein 65 induces proinflammatory cytokines but does not activate human mononuclear phagocytes. Scand J Immunol 39:613–617PubMedCrossRefGoogle Scholar
  75. Pockley AG, Muthana M, Calderwood SK (2008) The dual immunoregulatory role of stress proteins. Trends Biochem Sci 3:71–79Google Scholar
  76. Prakken BJ, Wauben MHM, van Kooten PJS, Anderton S, van der Zee R, Kuis W, van Eden W (1998) Nasal administration of arthritis related T cell epitopes of hsp60 as a promising way for immunotherapy in chronic arthritis. Biotherapy 10:205–211PubMedCrossRefGoogle Scholar
  77. Prakken BJ, Wendling U, van der Zee R, Rutten VPM, Kuis W, van Eden W (2001) Induction of IL-10 and inhibition of experimental arthritis are specific features of microbial heat shock proteins that are absent for other evolutionarily conserved immunodominant proteins. J Immunol 167:4147–4153PubMedGoogle Scholar
  78. Quintana FJ, Cohen IR (2005) Heat shock proteins as endogenous adjuvants in sterile and septic inflammation. J Immunol 175:2777–2782PubMedGoogle Scholar
  79. Ramirez SR, Singh-Jasuja H, Warger T, Braedel-Ruoff S, Hilf N, Wiemann K, Rammensee HG, Schild H (2005) Glycoprotein 96-activated dendritic cells induce a CD8-biased T-cell response. Cell Stress Chaperones 10:221–229PubMedCrossRefGoogle Scholar
  80. Raz I, Avron A, Tamir M, Metzger M, Symer L, Eldor R, Cohen IR, Elias D (2007) Treatment of new-onset type 1 diabetes with peptide DiaPep277 is safe and associated with preserved beta-cell function: extension of a randomized, double-blind, phase II trial. Diabetes Metab Res Rev 23:292–298PubMedCrossRefGoogle Scholar
  81. Reddi K, Meghji S, Wilson M, Henderson B (1995) Comparison of the osteolytic activity of surface-associated proteins of bacteria implicated in periodontal disease. Oral Dis 1:26–31PubMedCrossRefGoogle Scholar
  82. Reddi K, Meghji S, Nair SP, Arnett TR, Miller AD, Preuss M, Wilson M, Henderson B, Hill P (1998) The Escherichia coli chaperonin 60 (groEL) is a potent stimulator of osteoclast formation. J Bone Miner Res 13:1260–1266PubMedCrossRefGoogle Scholar
  83. Reed RC, Berwin B, Baker JP, Nicchitta CV (2003) GRP94/gp96 elicits ERK activation in murine macrophages. A role for endotoxin contamination in NF-κB activation and nitric oxide production. J Biol Chem 278:31853–31860PubMedCrossRefGoogle Scholar
  84. Rha YH, Taube C, Haczku A, Joetham A, Takeda K, Duez C, Siegel M, Aydintug MK, Born WK, Dakhama A, Gelfand EW (2002) Effect of microbial heat shock proteins on airway inflammation and hyperresponsiveness. J Immunol 169:5300–5307PubMedGoogle Scholar
  85. Riffo-Vasquez Y, Spina D, Page C, Desel C, Whelan M, Tormay P, Singh M, Henderson B, Coates ARM (2004) Differential effects of Mycobacterium tuberculosis chaperonins on bronchial eosinophilia and hyperresponsiveness in a murine model of allergic inflammation. Clin Exp Allergy 34:712–719PubMedCrossRefGoogle Scholar
  86. Rosser MF, Trotta BM, Marshall MR, Berwin B, Nicchitta CV (2004) Adenosine nucleotides and the regulation of GRP94-client protein interactions. Biochemistry 43:8835–8845PubMedCrossRefGoogle Scholar
  87. Sharp L, Ward JM, Poole S, Beighton D, Wilkins JC, Homer KA, Nair SP, Henderson B (2009) The periplasm of Escherichia coli contains cytokine-inducing proteins whose activity can be blocked by the lipopolysaccharide-inhibiting antibiotic, polymyxin B. Immunology, in pressGoogle Scholar
  88. Slack LK, Muthana M, Hopkinson K, Suvarna SK, Mirza S, Fairburn B, Pockley AG (2007) Administration of the stress protein gp96 prolongs rat cardiac allograft survival, modifies rejection-associated inflammatory events and induces a state of peripheral T cell hyporesponsiveness. Cell Stress Chaperones 12:71–82PubMedCrossRefGoogle Scholar
  89. Somerville JE Jr, Cassiano L, Bainbridge B, Cunningham MD, Darveau RP (1996) A novel Escherichia coli lipid A mutant that produces an antiinflammatory lipopolysaccharide. J Clin Invest 97:359–365PubMedCrossRefGoogle Scholar
  90. Srivastava PK (1997) Purification of heat shock protein-peptide complexes for use in vaccination against cancers and intracellular pathogens. Methods 12:165–171PubMedCrossRefGoogle Scholar
  91. Srivastava P (2002) Interaction of heat shock proteins with peptides and antigen presenting cells: chaperoning of the innate and adaptive immune responses. Ann Rev Immunol 20:395–425CrossRefGoogle Scholar
  92. Srivastava PK, Amato RJ (2001) Heat shock proteins: the 'Swiss Army Knife' vaccines against cancers and infectious agents. Vaccine 19:2590–2597PubMedCrossRefGoogle Scholar
  93. Srivastava PK, DeLeo AB, Old LJ (1986) Tumor rejection antigens of chemically induced sarcomas of inbred mice. Proc Natl Acad Sci USA 83:3407–3411PubMedCrossRefGoogle Scholar
  94. Strbo N, Oizumi S, Sotosek-Tokmadzic V, Podack ER (2003) Perforin is required for innate and adaptive immunity induced by heat shock protein gp96. Immunity 18:381–390PubMedCrossRefGoogle Scholar
  95. Tamura Y, Kutomi G, Oura J, Torigoe T, Noriyuki Sato N (2007) Piloting of exogenous antigen into cross-presentation pathway by heat shock proteins. In: Calderwood SK, Sherman MY, Ciocca DR (eds) Heat shock proteins in cancer. Springer, Dordrecht, pp 383–396CrossRefGoogle Scholar
  96. Thériault JR, Adachi H, Calderwood SK (2006) Role of scavenger receptors in the binding and internalization of heat shock protein 70. J Immunol 177:8604–8611PubMedGoogle Scholar
  97. Tormay P, Coates AR, Henderson B (2005) The intercellular signaling activity of the Mycobacterium tuberculosis chaperonin 60.1 protein resides in the equatorial domain. J Biol Chem 280:14272–14277PubMedCrossRefGoogle Scholar
  98. Triantafilou K, Triantafilou M, Dedrick RL (2001a) A CD14-independent LPS receptor cluster. Nat Immunol 2:338–345PubMedCrossRefGoogle Scholar
  99. Triantafilou K, Triantafilou M, Ladha S, Mackie A, Dedrick RL, Fernandez N, Cherry R (2001b) Fluorescence recovery after photobleaching reveals that LPS rapidly transfers from CD14 to hsp70 and hsp90 on the cell membrane. J Cell Sci 114:2535–2545PubMedGoogle Scholar
  100. Tsan MF, Gao B (2004) Endogenous ligands of Toll-like receptors. J Leukoc Biol 76:514–519PubMedCrossRefGoogle Scholar
  101. Tsan MF, Gao B (2009) Heat shock proteins and immune system. J Leukoc Biol 85:905–910PubMedCrossRefGoogle Scholar
  102. Vabulas RM, Ahmad-Nejad P, Ghose S, Kirschning CJ, Issels RD, Wagner H (2002a) HSP70 as endogenous stimulus of the Toll/interleukin-1 receptor signal pathway. J Biol Chem 277:15107–15112PubMedCrossRefGoogle Scholar
  103. Vabulas RM, Braedel S, Hilf N, Singh-Jasuja H, Herter S, Ahmad-Nejad P, Kirschning CJ, Da Costa C, Rammensee HG, Wagner H, Schild H (2002b) The endoplasmic reticulum-resident heat shock protein Gp96 activates dendritic cells via the Toll-like receptor 2/4 pathway. J Biol Chem 277:20847–20853PubMedCrossRefGoogle Scholar
  104. Vabulas RM, Wagner H, Schild H (2002c) Heat shock proteins as ligands of toll-like receptors. Cur Top Microbiol Immunol 270:169–184Google Scholar
  105. Valentinis B, Bianchi A, Zhou D, Cipponi A, Catalanotti F, Russo V, Traversari C (2005) Direct effects of polymyxin B on human dendritic cells maturation. The role of IκB-alpha/NF-κB and ERK1/2 pathways and adhesion. J Biol Chem 280:14264–14271PubMedCrossRefGoogle Scholar
  106. van der Zee R, van Eden W, Meloen RH, Noordzij A, Van Embden JD (1989) Efficient mapping and characterization of a T cell epitope by the simultaneous synthesis of multiple peptides. Eur J Immunol 19:43–47PubMedCrossRefGoogle Scholar
  107. van Eden W, Holoshitz J, Nevo Z, Frenkel A, Klajman A, Cohen IR (1985) Arthritis induced by a T-lymphocyte clone that responds to Mycobacterium tuberculosis and to cartilage proteoglycans. Proc Natl Acad Sci U S A 82:5117–5120PubMedCrossRefGoogle Scholar
  108. van Eden W, Thole JER, van der Zee R, Noordzij A, van Embden JDA, Hensen EJ, Cohen IR (1988) Cloning of the mycobacterial epitope recognized by T lymphocytes in adjuvant arthritis. Nature 331:171–173PubMedCrossRefGoogle Scholar
  109. van Eden W, van der Zee R, Prakken B (2005) Heat shock proteins induce T-cell regulation of chronic inflammation. Nat Immunol 5:318–330CrossRefGoogle Scholar
  110. van Puijvelde GH, Hauer AD, de Vos P, van den Heuvel R, van Herwijnen MJ, van der Zee R, van Eden W, van Berkel TJ, Kuiper J (2006) Induction of oral tolerance to oxidized low-density lipoprotein ameliorates atherosclerosis. Circulation 114:1968–1976PubMedCrossRefGoogle Scholar
  111. Vanags D, Williams B, Johnson B, Hall S, Nash P, Taylor A, Weiss J, Feeney D (2006) Therapeutic efficacy and safety of chaperonin 10 in patients with rheumatoid arthritis: a double-blind randomised trial. Lancet 368:855–863PubMedCrossRefGoogle Scholar
  112. Verdegaal ME, Zegveld ST, van Furth R (1996) Heat shock protein 65 induces CD62e, CD106, and CD54 on cultured human endothelial cells and increases their adhesiveness for monocytes and granulocytes. J Immunol 151:369–376Google Scholar
  113. Wallin RPA, Lundqvist A, Moré SH, von Bonin A, Kiessling R, Ljunggren H-G (2002) Heat-shock proteins as activators of the innate immune system. Trends Immunol 23:130–135PubMedCrossRefGoogle Scholar
  114. Wang Y, Kelly CG, Karttunen T, Whittall T, Lehner PJ, Duncan L, MacAry P, Younson JS, Singh M, Oehlmann W, Cheng G, Bergmeier L, Lehner T (2001) CD40 is a cellular receptor mediating mycobacterial heat shock protein 70 stimulation of CC-chemokines. Immunity 15:971–983PubMedCrossRefGoogle Scholar
  115. Wang Y, Gao B, Tsan MF (2005a) Induction of cytokines by heat shock proteins and concanavalin A in murine splenocytes. Cytokine 32:149–154PubMedCrossRefGoogle Scholar
  116. Wang Y, Whittall T, McGowan E, Younson J, Kelly C, Bergmeier LA, Singh M, Lehner T (2005b) Identification of stimulating and inhibitory epitopes within the heat shock protein 70 molecule that modulate cytokine production and maturation of dendritic cells. J Immunol 174:3306–3316PubMedGoogle Scholar
  117. Wang XY, Facciponte J, Chen X, Subjeck JR, Repasky EA (2007) Scavenger receptor-A negatively regulates antitumor immunity. Cancer Res 67:4996–5002PubMedCrossRefGoogle Scholar
  118. Warger T, Hilf N, Rechtsteiner G, Haselmayer P, Carrick DM, Jonuleit H, von Landenberg P, Rammensee HG, Nicchitta CV, Radsak MP, Schild H (2006) Interaction of TLR2 and TLR4 ligands with the N-terminal domain of Gp96 amplifies innate and adaptive immune responses. J Biol Chem 281:22545–22553PubMedCrossRefGoogle Scholar
  119. Wearsch PA, Nicchitta CV (1996) Purification and partial molecular characterization of GRP94, an ER resident chaperone. Protein Expr Purif 7:114–121PubMedCrossRefGoogle Scholar
  120. Wendling U, Paul L, van der Zee R, Prakken B, Singh M, van Eden W (2000) A conserved mycobacterial heat shock protein (hsp) 70 sequence prevents adjuvant arthritis upon nasal administration and induces IL-10-producing T cells that cross-react with the mammalian self-hsp70 homologue. J Immunol 164:2711–2717PubMedGoogle Scholar
  121. Williams B, Vanags D, Hall S, McCormack C, Foley P, Weiss J, Johnson B, Latz E, Feeney D (2008) Efficacy and safety of chaperonin 10 in patients with moderate to severe plaque psoriasis: evidence of utility beyond a single indication. Arch Dermatol 144:683–685PubMedCrossRefGoogle Scholar
  122. Winrow VR, Mesher J, Meghji S, Morris CJ, Maguire M, Fox S, Coates AR, Tormay P, Blake DR, Henderson B (2008) The two homologous chaperonin 60 proteins of Mycobacterium tuberculosis have distinct effects on monocyte differentiation into osteoclasts. Cell Microbiol 10:2091–2104PubMedCrossRefGoogle Scholar
  123. Yamazaki K, Nguyen T, Podack ER (1999) Tumour secreted heat shock-fusion protein elicits CD8 cells for rejection. J Immunol 163:5178–5182PubMedGoogle Scholar
  124. Ye Z, Gan YH (2007) Flagellin contamination of recombinant heat shock protein 70 is responsible for its activity on T cells. J Biol Chem 282:4479–4484PubMedCrossRefGoogle Scholar
  125. Young DB, Ivanyi J, Cox JH, Lamb JR (1987) The 65 kDa antigen of mycobacteria - a common bacterial protein? Immunol Today 8:215–219CrossRefGoogle Scholar
  126. Zanette D, Dundon W, Soffientini A, Sottani C, Marinelli F, Akeson A, Sarubbi E (1998) Human IL-1 receptor antagonist from Escherichia coli: large-scale microbial growth and protein purification. J Biotechnol 64:187–196PubMedCrossRefGoogle Scholar
  127. Zanin-Zhorov A, Nussbaum G, Franitza S, Cohen IR, Lider O (2003) T cells respond to heat shock protein 60 via TLR2: activation of adhesion and inhibition of chemokine receptors. FASEB J 17:1567–1569PubMedGoogle Scholar
  128. Zanin-Zhorov A, Bruck R, Tal G, Oren S, Aeed H, Hershkoviz R, Cohen IR, Lider O (2005a) Heat shock protein 60 inhibits Th1-mediated hepatitis model via innate regulation of Th1/Th2 transcription factors and cytokines. J Immunol 174:3227–3236PubMedGoogle Scholar
  129. Zanin-Zhorov A, Tal G, Shivtiel S, Cohen M, Lapidot T, Nussbaum G, Margalit R, Cohen IR, Lider O (2005b) Heat shock protein 60 activates cytokine-associated negative regulator suppressor of cytokine signaling 3 in T cells: effects on signaling, chemotaxis, and inflammation. J Immunol 175:276–285PubMedGoogle Scholar
  130. Zanin-Zhorov A, Cahalon L, Tal G, Margalit R, Lider O, Cohen IR (2006) Heat shock protein 60 enhances CD4+CD25+ regulatory T cell function via innate TLR2 signaling. J Clin Invest 116:2022–2032PubMedCrossRefGoogle Scholar
  131. Zanin-Zhorov A, Tal-Lapidot G, Cahalon L, Cohen-Sfady M, Pevsner-Fischer M, Lider O, Cohen IR (2007) Cutting edge: T cells respond to lipopolysaccharide innately via TLR4 signaling. J Immunol 179:41–44PubMedGoogle Scholar

Copyright information

© Cell Stress Society International 2009

Authors and Affiliations

  • Brian Henderson
    • 1
  • Stuart K. Calderwood
    • 2
  • Anthony R. M. Coates
    • 3
  • Irun Cohen
    • 4
  • Willem van Eden
    • 5
  • Thomas Lehner
    • 6
  • A. Graham Pockley
    • 7
  1. 1.Division of Microbial Diseases, UCL-Eastman Dental InstituteUniversity College LondonLondonUK
  2. 2.Department of Radiation Oncology, Beth Israel Deaconess Medical CenterHarvard Medical SchoolBostonUSA
  3. 3.Centre of Infection, Division of Cellular and Molecular MedicineSt. George’s University of LondonLondonUK
  4. 4.Department of ImmunologyThe Weizmann Institute of ScienceRehovotIsrael
  5. 5.Institute of Infectious Diseases and ImmunologyUtrecht UniversityUtrechtThe Netherlands
  6. 6.Kings College London at Guy’s HospitalLondonUK
  7. 7.Immunobiology Research Group, The Medical SchoolUniversity of SheffieldSheffieldUK

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