The Chaperokine Activity of Heat Shock Proteins

  • Punit Kaur
  • Alexzander A. A. AseaEmail author
Part of the Heat Shock Proteins book series (HESP, volume 16)


Enhanced expression of intracellular heat shock proteins (HSP) primarily promotes protein chaperoning, transport and folding of naïve, aberrantly folded, or mutated proteins, resulting in cytoprotection during variety of stressful stimuli. In contrast, exposure of immunocompetent cells to extracellular HSP activates antigen presenting cell-mediated effectors functions; including enhanced pro-inflammatory and anti-inflammatory responses, chemokine and costimulatory molecule expression and in anti-tumor surveillance. In addition, extracellular HSP has been shown to play a role in situations of both acute psychological stress and exercise. This chapter covers recent advances in understanding the complex nature of the chaperokine activity of HSP and briefly discusses the biological significance of circulating serum HSPA1A (Hsp70) to host physiology and includes recent application of HSPA1A (Hsp70)-based immunotherapies.


Chaperokine Heat shock proteins Inflammatory responses Signal transduction pathways 



Antigen presenting cells


Cytotoxic T lymphocytes


Inducible form of the 72 kDa heat shock protein


Constitutive form of the 73 kDa heat shock protein






Toll-like receptors



We thank all students, faculty and staff of the Asea Lab through the years. This work was supported in part the US National Institutes of Health grant RO1CA91889, Dana Faber Cancer Institute, Harvard Medical School, Boston University School of Medicine, Scott & White Hospital and Clinic, the Texas A&M Health Science Center College of Medicine, the Central Texas Veterans Health Administration, an Endowment from the Cain Foundation and the University of Toledo College of Medicine and Life Sciences (to A.A.). The funders had no role in study design, data collection and analysis, decision to publish or preparation of the chapter.


  1. Adewoye AH, McMahon L (2005) Chaperones and disease. N Engl J Med 353:2821–2822; author reply 2821-2822PubMedCrossRefGoogle Scholar
  2. Akide-Ndunge OB, Tambini E, Giribaldi G, McMillan PJ, Muller S, Arese P, Turrini F (2009) Co-ordinated stage-dependent enhancement of Plasmodium falciparum antioxidant enzymes and heat shock protein expression in parasites growing in oxidatively stressed or G6PD-deficient red blood cells. Malar J 8:113PubMedPubMedCentralCrossRefGoogle Scholar
  3. Asea A (2003) Chaperokine-induced signal transduction pathways. Exerc Immunol Rev 9:25–33PubMedPubMedCentralGoogle Scholar
  4. Asea A, Brown IR (2007) Heat shock proteins and the brain: implications for neurodegenerative diseases and neuroprotection. Springer, DordrechtGoogle Scholar
  5. Asea AA, Calderwood SK (2000) HSP70 binds to the cell surface of monocytes and induces cytokine expression. Cell Stress Chaperones 5:374–374CrossRefGoogle Scholar
  6. Asea P, Gunning JW (2002) AERC plenary session December 1999 – privatisation and corporate governance – preface. J Afr Econ 11:ii–iiGoogle Scholar
  7. Asea A, Ara G, Teicher BA, Stevenson MA, Calderwood SK (2000a) Effects of the flavnoid drug quercetin on the response of human prostate tumors to hyperthermia in vivo. Cell Stress Chaperones 5:500–500CrossRefGoogle Scholar
  8. Asea A, Ara G, Teicher BA, Calderwood SK (2000b) Cyclooxygenase inhibitors are potent sensitizers of DU-145 prostate tumors to hyperthermia in vivo. Cell Stress Chaperones 5:501–501CrossRefGoogle Scholar
  9. Asea A, Kabingu E, Stevenson MA, Calderwood SK (2000c) HSP70 peptide-bearing and peptide-negative preparations act as chaperokines. Cell Stress Chaperones 5:425–431PubMedPubMedCentralCrossRefGoogle Scholar
  10. Asea A, Kabingu E, Stevenson MA, Calderwood SK (2000d) Hsp70 peptide-bearing and peptide-negative preparations function as chaperokines. Cell Stress Chaperones 5:492–492CrossRefGoogle Scholar
  11. Asea A, Kabingu E, Stevenson MA, Calderwood SK (2000e) HSP70 peptidembearing and peptide-negative preparations act as chaperokines. Cell Stress Chaperones 5:425–431PubMedPubMedCentralCrossRefGoogle Scholar
  12. Asea A, Kraeft SK, Kurt-Jones EA, Stevenson MA, Chen LB, Finberg RW, Koo GC, Calderwood SK (2000f) HSP70 stimulates cytokine production through a CD14-dependant pathway, demonstrating its dual role as a chaperone and cytokine. Nat Med 6:435–442PubMedCrossRefGoogle Scholar
  13. Asea A, Kraeft SK, Kurt-Jones EA, Stevenson MA, Chen LB, Finberg RW, Koo GC, Calderwood SK (2000g) Hsp70 stimulates cytokine production via a CD14-dependent pathway: a “chaperokine”. Cell Stress Chaperones 5:491–491CrossRefGoogle Scholar
  14. Asea A, Rehli M, Kabingu E, Boch JA, Bare O, Auron PE, Stevenson MA, Calderwood SK (2002a) Novel signal transduction pathway utilized by extracellular HSP70 – role of toll-like receptor (TLR) 2 AND TLR4. J Biol Chem 277:15028–15034PubMedPubMedCentralCrossRefGoogle Scholar
  15. Asea A, Rehli M, Kabingu E, Boch JA, Bare O, Auron PE, Stevenson MA, Calderwood SK (2002b) Novel signal transduction pathway utilized by extracellular HSP70: role of toll-like receptor (TLR) 2 and TLR4. J Biol Chem 277:15028–15034PubMedPubMedCentralCrossRefGoogle Scholar
  16. Barreto A, Gonzalez JM, Kabingu E, Asea A, Fiorentino S (2003) Stress-induced release of HSC70 from human tumors. Cell Immunol 222:97–104PubMedCrossRefGoogle Scholar
  17. Bausero MA, Gastpar R, Multhoff G, Asea A (2005) Alternative mechanism by which IFN-gamma enhances tumor recognition: active release of heat shock protein 72. J Immunol 175:2900–2912PubMedPubMedCentralCrossRefGoogle Scholar
  18. Becker T, Hartl FU, Wieland F (2002) CD40, an extracellular receptor for binding and uptake of Hsp70-peptide complexes. J Cell Biol 158:1277–1285PubMedPubMedCentralCrossRefGoogle Scholar
  19. Bergmeier LA, Babaahmady K, Pido-Lopez J, Heesom KJ, Kelly CG, Lehner T (2010) Cytoskeletal proteins bound to heat-shock protein 70 may elicit resistance to simian immunodeficiency virus infection of CD4(+) T cells. Immunology 129:506–515PubMedPubMedCentralCrossRefGoogle Scholar
  20. Binder RJ, Anderson KM, Basu S, Srivastava PK (2000) Cutting edge: heat shock protein gp96 induces maturation and migration of CD11c+ cells in vivo. J Immunol 165:6029–6035PubMedCrossRefGoogle Scholar
  21. Binder RJ, Karimeddini D, Srivastava PK (2001a) Adjuvanticity of alpha 2-macroglobulin, an independent ligand for the heat shock protein receptor CD91. J Immunol 166:4968–4972PubMedCrossRefGoogle Scholar
  22. Binder RJ, Blachere NE, Srivastava PK (2001b) Heat shock protein-chaperoned peptides but not free peptides introduced into the cytosol are presented efficiently by major histocompatibility complex I molecules. J Biol Chem 276:17163–17171PubMedCrossRefGoogle Scholar
  23. Boudesco C, Cause S, Jego G, Garrido C (2018) Hsp70: a cancer target inside and outside the cell. Methods Mol Biol 1709:371–396PubMedCrossRefPubMedCentralGoogle Scholar
  24. Calderwood SK, Neckers L (2016) Hsp90 in cancer: transcriptional roles in the nucleus. Adv Cancer Res 129:89–106PubMedCrossRefPubMedCentralGoogle Scholar
  25. Calderwood SK, Mambula SS, Gray PJ Jr (2007a) Extracellular heat shock proteins in cell signaling and immunity. Ann N Y Acad Sci 1113:28–39PubMedCrossRefPubMedCentralGoogle Scholar
  26. Calderwood SK, Mambula SS, Gray PJ Jr, Theriault JR (2007b) Extracellular heat shock proteins in cell signaling. FEBS Lett 581:3689–3694PubMedCrossRefGoogle Scholar
  27. Calderwood SK, Sherman ML, Ciocca DR (2007c) Heat shock proteins in cancer. Springer, DordrechtCrossRefGoogle Scholar
  28. Calderwood SK, Sherman MY, Ciocca D (2007d) Heat shock proteins in cancer. Springer, DordrechtCrossRefGoogle Scholar
  29. Calderwood SK, Sherman YM, Ciocca D (2007e) Heat shock proteins in cancer. Springer, DordrechtCrossRefGoogle Scholar
  30. Calderwood SK, Sherman MY, Ciocca DR (2007f) Heat shock proteins in cancer. Springer, DordrechtCrossRefGoogle Scholar
  31. Calderwood SK, Theriault J, Gray PJ, Gong J (2007g) Cell surface receptors for molecular chaperones. Methods 43:199–206PubMedCrossRefGoogle Scholar
  32. Calderwood SK, Murshid A, Prince T (2009) The shock of aging: molecular chaperones and the heat shock response in longevity and aging – a mini-review. Gerontology 55:550–558PubMedPubMedCentralCrossRefGoogle Scholar
  33. Calderwood SK, Gong J, Murshid A (2016) Extracellular HSPs: the complicated roles of extracellular HSPs in immunity. Front Immunol 7:159PubMedPubMedCentralGoogle Scholar
  34. Campisi J, Fleshner M (2003) Role of extracellular HSP72 in acute stress-induced potentiation of innate immunity in active rats. J Appl Physiol 94:43–52PubMedCrossRefPubMedCentralGoogle Scholar
  35. Campisi J, Hansen MK, O'Connor KA, Biedenkapp JC, Watkins LR, Maier SF, Fleshner M (2003a) Circulating cytokines and endotoxin are not necessary for the activation of the sickness or corticosterone response produced by peripheral E. coli challenge. J Appl Physiol 95:1873–1882PubMedCrossRefPubMedCentralGoogle Scholar
  36. Campisi J, Leem TH, Fleshner M (2003b) Stress-induced extracellular Hsp72 is a functionally significant danger signal to the immune system. Cell Stress Chaperones 8:272–286PubMedPubMedCentralCrossRefGoogle Scholar
  37. Campisi J, Leem TH, Greenwood BN, Hansen MK, Moraska A, Higgins K, Smith TP, Fleshner M (2003c) Habitual physical activity facilitates stress-induced HSP72 induction in brain, peripheral, and immune tissues. Am J Phys Regul Integr Comp Phys 284:R520–R530Google Scholar
  38. Clayton A, Turkes A, Navabi H, Mason MD, Tabi Z (2005) Induction of heat shock proteins in B-cell exosomes. J Cell Sci 118:3631–3638PubMedCrossRefGoogle Scholar
  39. 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
  40. van Eden W (2006) Immunoregulation of autoimmune diseases. Hum Immunol 67:446–453PubMedCrossRefGoogle Scholar
  41. Effros RB, Zhu X, Walford RL (1994) Stress response of senescent T lymphocytes: reduced hsp70 is independent of the proliferative block. J Gerontol 49:B65–B70PubMedCrossRefGoogle Scholar
  42. Escola JM, Kleijmeer MJ, Stoorvogel W, Griffith JM, Yoshie O, Geuze HJ (1998) Selective enrichment of tetraspan proteins on the internal vesicles of multivesicular endosomes and on exosomes secreted by human B-lymphocytes. J Biol Chem 273:20121–20127PubMedCrossRefGoogle Scholar
  43. Farkas B, Hantschel M, Magyarlaki M, Becker B, Scherer K, Landthaler M, Pfister K, Gehrmann M, Gross C, Mackensen A, Multhoff G (2003) Heat shock protein 70 membrane expression and melanoma-associated marker phenotype in primary and metastatic melanoma. Melanoma Res 13:147–152PubMedCrossRefGoogle Scholar
  44. Faure O, Graff-Dubois S, Bretaudeau L, Derre L, Gross DA, Alves PM, Cornet S, Duffour MT, Chouaib S, Miconnet I, Gregoire M, Jotereau F, Lemonnier FA, Abastado JP, Kosmatopoulos K (2004) Inducible Hsp70 as target of anticancer immunotherapy: identification of HLA-A*0201-restricted epitopes. Int J Cancer 108:863–870PubMedCrossRefGoogle Scholar
  45. Gardiner G, Guindon L, Perez L, Evans-Molina C, Blum J (2015) Heat shock protein 90, a potential biomarker for type I diabetes, is secreted by human pancreatic beta cells in response to cytokine stress (BA7P.161). J Immunol 194:115.21Google Scholar
  46. Gastpar R, Gehrmann M, Bausero MA, Asea A, Gross C, Schroeder JA, Multhoff G (2005) Heat shock protein 70 surface-positive tumor exosomes stimulate migratory and cytolytic activity of natural killer cells. Cancer Res 65:5238–5247PubMedPubMedCentralCrossRefGoogle Scholar
  47. Gehrmann M, Schmetzer H, Eissner G, Haferlach T, Hiddemann W, Multhoff G (2003) Membrane-bound heat shock protein 70 (Hsp70) in acute myeloid leukemia: a tumor specific recognition structure for the cytolytic activity of autologous NK cells. Haematologica 88:474–476PubMedGoogle Scholar
  48. Gordon NF, Clark BL (2004) The challenges of bringing autologous HSP-based vaccines to commercial reality. Methods 32:63–69PubMedCrossRefGoogle Scholar
  49. Gross C, Hansch D, Gastpar R, Multhoff G (2003a) Interaction of heat shock protein 70 peptide with NK cells involves the NK receptor CD94. Biol Chem 384:267–279PubMedCrossRefGoogle Scholar
  50. Gross C, Koelch W, DeMaio A, Arispe N, Multhoff G (2003b) Cell surface-bound heat shock protein 70 (Hsp70) mediates perforin-independent apoptosis by specific binding and uptake of granzyme B. J Biol Chem 278:41173–41181PubMedCrossRefGoogle Scholar
  51. Gross C, Schmidt-Wolf IG, Nagaraj S, Gastpar R, Ellwart J, Kunz-Schughart LA, Multhoff G (2003c) Heat shock protein 70-reactivity is associated with increased cell surface density of CD94/CD56 on primary natural killer cells. Cell Stress Chaperones 8:348–360PubMedPubMedCentralCrossRefGoogle Scholar
  52. Gross C, Holler E, Stangl S, Dickinson A, Pockley AG, Asea AA, Mallappa N, Multhoff G (2008a) An Hsp70 peptide initiates NK cell killing of leukemic blasts after stem cell transplantation. Leuk Res 32:527–534PubMedCrossRefGoogle Scholar
  53. Gross M, Ramirez C, Luthringer D, Nepomuceno E, Vollmer R, Burchette J, Freedland SJ (2008b) Expression of androgen and estrogen related proteins in normal weight and obese prostate cancer patients. Prostate 69:520–527CrossRefGoogle Scholar
  54. Guzhova I, Kislyakova K, Moskaliova O, Fridlanskaya I, Tytell M, Cheetham M, Margulis B (2001) In vitro studies show that Hsp70 can be released by glia and that exogenous Hsp70 can enhance neuronal stress tolerance. Brain Res 914:66–73PubMedCrossRefGoogle Scholar
  55. Hightower LE, Guidon PT Jr (1989) Selective release from cultured mammalian cells of heat-shock (stress) proteins that resemble glia-axon transfer proteins. J Cell Physiol 138:257–266PubMedCrossRefGoogle Scholar
  56. Hori S, Nomura T, Sakaguchi S (2003a) Control of regulatory T cell development by the transcription factor Foxp3. Science 299:1057–1061PubMedPubMedCentralCrossRefGoogle Scholar
  57. Hori S, Takahashi T, Sakaguchi S (2003b) Control of autoimmunity by naturally arising regulatory CD4+ T cells. Adv Immunol 81:331–371PubMedCrossRefGoogle Scholar
  58. Hsu DH, Paz P, Villaflor G, Rivas A, Mehta-Damani A, Angevin E, Zitvogel L, Le Pecq JB (2003) Exosomes as a tumor vaccine: enhancing potency through direct loading of antigenic peptides. J Immunother 26:440–450PubMedCrossRefGoogle Scholar
  59. Hunter-Lavin C, Hudson PR, Mukherjee S, Davies GK, Williams CP, Harvey JN, Child DF, Williams JH (2004) Folate supplementation reduces serum hsp70 levels in patients with type 2 diabetes. Cell Stress Chaperones 9:344–349PubMedPubMedCentralCrossRefGoogle Scholar
  60. Jin X, Wang R, Xiao C, Cheng L, Wang F, Yang L, Feng T, Chen M, Chen S, Fu X, Deng J, Wang R, Tang F, Wei Q, Tanguay RM, Wu T (2004) Serum and lymphocyte levels of heat shock protein 70 in aging: a study in the normal Chinese population. Cell Stress Chaperones 9:69–75PubMedPubMedCentralCrossRefGoogle Scholar
  61. Kawabata Y, Udono H, Honma K, Ueda M, Mukae H, Kadota J, Kohno S, Yui K (2002) Merozoite surface protein 1-specific immune response is protective against exoerythrocytic forms of Plasmodium yoelii. Infect Immun 70:6075–6082PubMedPubMedCentralCrossRefGoogle Scholar
  62. Kempaiah P, Dokladny K, Karim Z, Raballah E, Achieng AO, Ong'echa JM, Moseley PL, Lambert CG, Perkins DJ (2017) Reduced HSP70 and glutamine in pediatric severe malaria anemia: role of hemozoin in suppressing HSP70 and NF-κb activation. Am J Trop Med Hyg 97:517–518Google Scholar
  63. Kim WS, Jung ID, Kim JS, Kim HM, Kwon KW, Park YM, Shin SJ (2018) Mycobacterium tuberculosis GrpE, a heat-shock stress responsive chaperone, promotes Th1-biased T cell immune response via TLR4-mediated activation of dendritic cells. Front Cell Infect Microbiol 8:95PubMedPubMedCentralCrossRefGoogle Scholar
  64. Kleinjung T, Arndt O, Feldmann HJ, Bockmuhl U, Gehrmann M, Zilch T, Pfister K, Schonberger J, Marienhagen J, Eilles C, Rossbacher L, Multhoff G (2003) Heat shock protein 70 (Hsp70) membrane expression on head-and-neck cancer biopsy-a target for natural killer (NK) cells. Int J Radiat Oncol Biol Phys 57:820–826PubMedCrossRefGoogle Scholar
  65. Lackie RE, Maciejewski A, Ostapchenko VG, Marques-Lopes J, Choy WY, Duennwald ML, Prado VF, Prado MAM (2017) The Hsp70/Hsp90 chaperone machinery in neurodegenerative diseases. Front Neurosci 11:254PubMedPubMedCentralCrossRefGoogle Scholar
  66. Lehner T, Anton PA (2002) Mucosal immunity and vaccination against HIV. AIDS 16(Suppl 4):S125–S132PubMedCrossRefGoogle Scholar
  67. Manjili MH, Henderson R, Wang XY, Chen X, Li Y, Repasky E, Kazim L, Subjeck JR (2002a) Development of a recombinant HSP110-HER-2/neu vaccine using the chaperoning properties of HSP110. Cancer Res 62:1737–1742PubMedGoogle Scholar
  68. Manjili MH, Wang XY, Park J, Facciponte JG, Repasky EA, Subjeck JR (2002b) Immunotherapy of cancer using heat shock proteins. Front Biosci 7:d43–d52PubMedCrossRefGoogle Scholar
  69. Manjili MH, Wang XY, Park J, Macdonald IJ, Li Y, Van Schie RC, Subjeck JR (2002c) Cancer immunotherapy: stress proteins and hyperthermia. Int J Hyperth 18:506–520CrossRefGoogle Scholar
  70. Manjili MH, Wang XY, Chen X, Martin T, Repasky EA, Henderson R, Subjeck JR (2003) HSP110-HER2/neu chaperone complex vaccine induces protective immunity against spontaneous mammary tumors in HER-2/neu transgenic mice. J Immunol 171:4054–4061PubMedCrossRefGoogle Scholar
  71. Marcus R, Culver DH, Bell DM, Srivastava PU, Mendelson MH, Zalenski RJ, Farber B, Fligner D, Hassett J, Quinn TC et al (1993) Risk of human immunodeficiency virus infection among emergency department workers. Am J Med 94:363–370PubMedCrossRefGoogle Scholar
  72. Mazzaferro V, Coppa J, Carrabba MG, Rivoltini L, Schiavo M, Regalia E, Mariani L, Camerini T, Marchiano A, Andreola S, Camerini R, Corsi M, Lewis JJ, Srivastava PK, Parmiani G (2003) Vaccination with autologous tumor-derived heat-shock protein gp96 after liver resection for metastatic colorectal cancer. Clin Cancer Res 9:3235–3245PubMedPubMedCentralGoogle Scholar
  73. Moser C, Schmidbauer C, Gurtler U, Gross C, Gehrmann M, Thonigs G, Pfister K, Multhoff G (2002) Inhibition of tumor growth in mice with severe combined immunodeficiency is mediated by heat shock protein 70 (Hsp70)-peptide-activated, CD94 positive natural killer cells. Cell Stress Chaperones 7:365–373PubMedPubMedCentralCrossRefGoogle Scholar
  74. Multhoff G (2006) Heat shock proteins in immunity. Handb Exp Pharmacol 172:279–304CrossRefGoogle Scholar
  75. Multhoff G (2007) Heat shock protein 70 (Hsp70): membrane location, export and immunological relevance. Methods 43:229–237PubMedCrossRefGoogle Scholar
  76. Multhoff G, Pfister K, Gehrmann M, Hantschel M, Gross C, Hafner M, Hiddemann W (2001) A 14-mer Hsp70 peptide stimulates natural killer (NK) cell activity. Cell Stress Chaperones 6:337–344PubMedPubMedCentralCrossRefGoogle Scholar
  77. Murshid A, Gong J, Stevenson MA, Calderwood SK (2011a) Heat shock proteins and cancer vaccines: developments in the past decade and chaperoning in the decade to come. Expert Rev Vaccines 10:1553–1568PubMedPubMedCentralCrossRefGoogle Scholar
  78. Murshid A, Theriault J, Gong J, Calderwood SK (2011b) Investigating receptors for extracellular heat shock proteins. Methods Mol Biol 787:289–302PubMedPubMedCentralCrossRefGoogle Scholar
  79. Neckers L, Blagg B, Haystead T, Trepel JB, Whitesell L, Picard D (2018) Methods to validate Hsp90 inhibitor specificity, to identify off-target effects, and to rethink approaches for further clinical development. Cell Stress Chaperones 23:467–482PubMedPubMedCentralCrossRefGoogle Scholar
  80. van Noort JM, Bugiani M, Amor S (2017) Heat shock proteins: old and novel roles in neurodegenerative diseases in the central nervous system. CNS Neurol Disord Drug Targets 16:244–256PubMedCrossRefGoogle Scholar
  81. Panjwani NN, Popova L, Srivastava PK (2002) Heat shock proteins gp96 and hsp70 activate the release of nitric oxide by APCs. J Immunol 168:2997–3003PubMedCrossRefGoogle Scholar
  82. Prado M (2017) New mechanisms regulating neuronal resilience in neurodegeneration. J Neurochem 142:24CrossRefGoogle Scholar
  83. Sato K, Torimoto Y, Tamura Y, Shindo M, Shinzaki H, Hirai K, Kohgo Y (2001) Immunotherapy using heat-shock protein preparations of leukemia cells after syngeneic bone marrow transplantation in mice. Blood 98:1852–1857PubMedCrossRefGoogle Scholar
  84. Schneider EM, Niess AM, Lorenz I, Northoff H, Fehrenbach E (2002) Inducible hsp70 expression analysis after heat and physical exercise: transcriptional, protein expression, and subcellular localization. Ann N Y Acad Sci 973:8–12PubMedCrossRefGoogle Scholar
  85. Sevin M, Girodon F, Garrido C, de Thonel A (2015) HSP90 and HSP70: implication in inflammation processes and therapeutic approaches for myeloproliferative neoplasms. Mediat Inflamm 2015:970242CrossRefGoogle Scholar
  86. Srivastava P (2002a) Interaction of heat shock proteins with peptides and antigen presenting cells: chaperoning of the innate and adaptive immune responses. Annu Rev Immunol 20:395–425PubMedCrossRefGoogle Scholar
  87. Srivastava P (2002b) Roles of heat-shock proteins in innate and adaptive immunity. Nat Rev Immunol 2:185–194PubMedCrossRefPubMedCentralGoogle Scholar
  88. Srivastava P (2004) Heat shock proteins and immune response: methods to madness. Methods 32:1–2PubMedCrossRefGoogle Scholar
  89. Srivastava PK, DeLeo AB, Old LJ (1986) Tumor rejection antigens of chemically induced sarcomas of inbred mice. Proc Natl Acad Sci U S A 83:3407–3411PubMedPubMedCentralCrossRefGoogle Scholar
  90. Stangl S, Gross C, Pockley AG, Asea AA, Multhoff G (2008) Influence of Hsp70 and HLA-E on the killing of leukemic blasts by cytokine/Hsp70 peptide-activated human natural killer (NK) cells. Cell Stress Chaperones 13:221–230PubMedPubMedCentralCrossRefGoogle Scholar
  91. Stangl S, Gehrmann M, Dressel R, Alves F, Dullin C, Themelis G, Ntziachristos V, Staeblein E, Walch A, Winkelmann I, Multhoff G (2011a) In vivo imaging of CT26 mouse tumours by using cmHsp70.1 monoclonal antibody. J Cell Mol Med 15:874–887PubMedCrossRefGoogle Scholar
  92. Stangl S, Gehrmann M, Riegger J, Kuhs K, Riederer I, Sievert W, Hube K, Mocikat R, Dressel R, Kremmer E, Pockley AG, Friedrich L, Vigh L, Skerra A, Multhoff G (2011b) Targeting membrane heat-shock protein 70 (Hsp70) on tumors by cmHsp70.1 antibody. Proc Natl Acad Sci U S A 108:733–738PubMedCrossRefGoogle Scholar
  93. Stangl S, Themelis G, Friedrich L, Ntziachristos V, Sarantopoulos A, Molls M, Skerra A, Multhoff G (2011c) Detection of irradiation-induced, membrane heat shock protein 70 (Hsp70) in mouse tumors using Hsp70 Fab fragment. Radiother Oncol 99:313–316PubMedCrossRefGoogle Scholar
  94. Swaroop S (2017) HSP60 plays a regulatory role in IL-1β-induced microglial inflammation via TLR4-p38 MAPK axis. J Neurochem 142:104Google Scholar
  95. Tamura Y, Peng P, Liu K, Daou M, Srivastava PK (1997) Immunotherapy of tumors with autologous tumor-derived heat shock protein preparations. Science 278:117–120PubMedCrossRefGoogle Scholar
  96. Terry DF, Wilcox M, McCormick MA, Lawler E, Perls TT (2003) Cardiovascular advantages among the offspring of centenarians. J Gerontol A Biol Sci Med Sci 58:M425–M431PubMedCrossRefGoogle Scholar
  97. Theriault JR, Mambula SS, Sawamura T, Stevenson MA, Calderwood SK (2005) Extracellular HSP70 binding to surface receptors present on antigen presenting cells and endothelial/epithelial cells. FEBS Lett 579:1951–1960PubMedCrossRefPubMedCentralGoogle Scholar
  98. Theriault JR, Adachi H, Calderwood SK (2006) Role of scavenger receptors in the binding and internalization of heat shock protein 70. J Immunol 177:8604–8611PubMedCrossRefPubMedCentralGoogle Scholar
  99. Walsh RC, Koukoulas I, Garnham A, Moseley PL, Hargreaves M, Febbraio MA (2001) Exercise increases serum Hsp72 in humans. Cell Stress Chaperones 6:386–393PubMedPubMedCentralCrossRefGoogle Scholar
  100. Wang XY, Kazim L, Repasky EA, Subjeck JR (2001) Characterization of heat shock protein 110 and glucose-regulated protein 170 as cancer vaccines and the effect of fever-range hyperthermia on vaccine activity. J Immunol 166:490–497PubMedCrossRefGoogle Scholar
  101. Wang Y, Kelly CG, Singh M, McGowan EG, Carrara AS, Bergmeier LA, Lehner T (2002) Stimulation of Th1-polarizing cytokines, C-C chemokines, maturation of dendritic cells, and adjuvant function by the peptide binding fragment of heat shock protein 70. J Immunol 169:2422–2429PubMedCrossRefGoogle Scholar
  102. Whittall T, Peters B, Rahman D, Kingsley CI, Vaughan R, Lehner T (2011) Immunogenic and tolerogenic signatures in human immunodeficiency virus (HIV)-infected controllers compared with progressors and a conversion strategy of virus control. Clin Exp Immunol 166:208–217PubMedPubMedCentralCrossRefGoogle Scholar
  103. Wu B, Gu MJ, Heydari AR, Richardson A (1993) The effect of age on the synthesis of two heat shock proteins in the hsp70 family. J Gerontol 48:B50–B56PubMedCrossRefGoogle Scholar
  104. 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 174:3227–3236PubMedCrossRefGoogle Scholar
  105. 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 175:276–285PubMedCrossRefGoogle Scholar
  106. Zhou Y, Ma J, Zhang J, He L, Gong J, Long C (2017) Pifithrin-mu is efficacious against non-small cell lung cancer via inhibition of heat shock protein 70. Oncol Rep 37:313–322PubMedCrossRefGoogle Scholar
  107. Zitvogel L, Fernandez N, Lozier A, Wolfers J, Regnault A, Raposo G, Amigorena S (1999) Dendritic cells or their exosomes are effective biotherapies of cancer. Eur J Cancer 35(Suppl 3):S36–S38PubMedCrossRefGoogle Scholar

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© Springer Nature Switzerland AG 2019

Authors and Affiliations

  1. 1.Department of Experimental Radiation OncologyMD Anderson Cancer CenterHoustonUSA
  2. 2.Department of Medicine and Director, Precision Therapeutics Proteogenomics Diagnostic Center, Eleanor N. Dana Cancer CenterUniversity of Toledo College of Medicine and Life SciencesToledoUSA

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