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Circulating HSP70 as an Endogenous Cytoprotector?

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Heat Shock Proteins and Whole Body Physiology

Part of the book series: Heat Shock Proteins ((HESP,volume 5))

Abstracts

Although classically regarded as being an intracellular molecular chaperone, many studies have reported that the 70 kDa stress protein can be released from a number of different cell types in the absence of cell death. Furthermore, we and others have reported the presence of Hsp70 in the circulation of normal individuals, and levels of this protein in the peripheral circulation can be increased by a number of physical and psychological stressors. The question is: what is the physiological role of circulating Hsp70? Extracellular Hsp70 has been reported to have a number of neuroprotective and cytoprotective properties, and we have shown that high serum levels of Hsp70 protect individuals with hypertension from the development and progression of cardiovascular disease. It might therefore be that extracellular members of the 70 kDa stress protein family have multiple roles in the maintenance of physiological homeostasis which extend beyond their more commonly accepted properties as immunoregulatory molecules. Perhaps this ubiquitous family of stress proteins could also be considered as exogenous cytoprotectors.

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Abbreviations

Hsp70:

seventy kilo-dalton heat shock protein

HUVECs:

human umbilical vein endothelial cells

IL-6:

interleukin-6

TLR:

toll like receptor

TNF-α:

tumour necrosis factor-α

References

  • Ahn, J. H., Ko, Y. G., Park, W. Y., Kang, Y. S., Chung, H. Y. and Seo, J. S. (1999) Suppression of ceramide-mediated apoptosis by HSP70. Mol Cells 9, 200–206.

    CAS  PubMed  Google Scholar 

  • Bassan, M., Zamostiano, R., Giladi, E. et al. (1998) The identification of secreted heat shock 60-like protein from rat glial cells and a human neuroblastoma cell line. Neurosci Lett 250, 37–40.

    Article  CAS  PubMed  Google Scholar 

  • Bausero, M. A., Gastpar, R., Multhoff, G. and Asea, A. (2005) Alternative mechanism by which IFN-gamma enhances tumor recognition: active release of heat shock protein 72. J Immunol 175, 2900–2912.

    CAS  PubMed  Google Scholar 

  • Berberian, P., Johnson, A. and Bond, M. (1990) Exogenous 70 kD heat shock protein increases survival of normal and atheromatous arterial cells. FASEB J 4, A1031.

    Google Scholar 

  • Bernstein, S. L., Liu, A. M., Hansen, B. C. and Somiari, R. I. (2000) Heat shock cognate-70 gene expression declines during normal aging of the primate retina. Invest Ophthalmol Vis Sci 10, 2857–2862.

    Google Scholar 

  • Broquet, A. H., Thomas, G., Masliah, J., Trugnan, G. and Bachelet, M. (2003) Expression of the molecular chaperone Hsp70 in detergent-resistant microdomains correlates with its membrane delivery and release. J Biol Chem 278, 21601–21606.

    Article  CAS  PubMed  Google Scholar 

  • Chimini, C. and Rubartelli, A.. Novel pathways of protein secretion. In: Molecular Chaperones and Cell Signalling, B. Henderson, and A. G. Pockley, eds. Cambridge University Press, New York, 2005, pp. 45–60.

    Chapter  Google Scholar 

  • Effros, R. B., Zhu, X. and Walford, R. L. (1994) Stress response of senescent T lymphocytes: reduced hsp70 is independent of the proliferative block. J Gerontol 49, B65–B70.

    CAS  PubMed  Google Scholar 

  • Evdonin, A. L., Guzhova, I. V., Margulis, B. A. and Medvedeva, N. D. (2004) Phospholipase C inhibitor, U73122, stimulates release of hsp-70 stress protein from A431 human carcinoma cells. Cancer Cell Int 4, 2.

    Article  PubMed  Google Scholar 

  • Evdonin, A. L., Martynova, M. G., Bystrova, O. A., Guzhova, I. V., Margulis, B. A. and Medvedeva, N. D. (2006) The release of Hsp70 from A431 carcinoma cells is mediated by secretory-like granules. Eur J Cell Biol 85, 443–455.

    Article  CAS  PubMed  Google Scholar 

  • Faassen, A. E., O’Leary, J. J., Rodysill, K. J., Bergh, N. and Hallgren, H. M. (1989) Diminished heat-shock protein synthesis following mitogen stimulation of lymphocytes from aged donors. Exp Cell Res 183, 326–334.

    Article  CAS  PubMed  Google Scholar 

  • Fargnoli, J., Kunisada, T., Fornace, A. J. J., Schneider, E. L. and Holbrook, N. J. (1990) Decreased expression of heat shock protein 70 mRNA and protein after heat treatment in cells of aged rats. Proc Natl Acad Sci U S A 87, 846–850.

    Article  CAS  PubMed  Google Scholar 

  • Febbraio, M. A., Ott, P., Nielsen, H. B. et al. (2002) Exercise induces hepatosplanchnic release of heat shock protein 72 in humans. J Physiol 544, 957–962.

    Article  CAS  PubMed  Google Scholar 

  • Fehrenbach, E., Niess, A. M., Voelker, K., Northoff, H. and Mooren, F. C. (2005) Exercise intensity and duration affect blood soluble HSP72. Int J Sports Med 26, 552–557.

    Article  CAS  PubMed  Google Scholar 

  • Fleshner, M., Campisi, J., Amiri, L. and Diamond, D. M. (2004) Cat exposure induces both intra- and extracellular Hsp72: the role of adrenal hormones. Psychoneuroendocrinology 29, 1142–1152.

    Article  CAS  PubMed  Google Scholar 

  • Gastpar, R., Gehrmann, M., Bausero, M. A. et al. (2005) Heat shock protein 70 surface-positive tumor exosomes stimulate migratory and cytolytic activity of natural killer cells. Cancer Res 65, 5238–5247.

    Article  CAS  PubMed  Google Scholar 

  • Gray, C. C., Amrani, M., Smolenski, R. T., Taylor, G. I. and Yacoub, M. H. (2000) Age dependence of heat stress mediated cardioprotection. Ann Thoracic Surg 2, 621–626.

    Article  Google Scholar 

  • Guzhova, I., Kislyakova, K., Moskaliova, O. et al. (2001) In vitro studies show that Hsp70 can be released by glia and that exogenous Hsp70 can enhance neuronal stress tolerance. Brain Res 914, 66–73.

    Article  CAS  PubMed  Google Scholar 

  • Hall, D., Xu, L., Drake, V. J. et al. (2000) Aging reduces adaptive capacity and stress protein expression in the liver after heat stress. J Appl Physiol 2, 749–759.

    Google Scholar 

  • Hartl, F. U. (1996) Molecular chaperones in cellular protein folding. Nature 381, 571–579.

    Article  CAS  PubMed  Google Scholar 

  • Heydari, A. R., Conrad, C. C. and Richardson, A. (1995) Expression of heat shock genes in hepatocytes is affected by age and food restriction in rats. J Nutr 125, 410–418.

    CAS  PubMed  Google Scholar 

  • Hightower, L. E. (1991) Heat shock, stress proteins, chaperones and proteotoxicity. Cell 66, 191–197.

    Article  CAS  PubMed  Google Scholar 

  • Hightower, L. E. and Guidon, P. T. (1989) Selective release from cultured mammalian cells of heat-shock (stress) proteins that resemble glia-axon transfer proteins. J Cell Physiol 138, 257–266.

    Article  CAS  PubMed  Google Scholar 

  • Jäättelä, M., Wissing, D., Bauer, P. A. and Li, G. C. (1992) Major heat shock protein hsp70 protects tumor cells from tumor necrosis factor cytotoxicity. EMBO J 11, 3507–3512.

    PubMed  Google Scholar 

  • Jin, X., Wang, R., Xiao, C. et al. (2004) Serum and lymphocyte levels of heat shock protein 70 in aging: a study in the normal Chinese population. Cell Stress Chaperones 9, 69–75.

    CAS  PubMed  Google Scholar 

  • Johnson, A. D., Berberian, P. A. and Bond, M. G. (1990) Effect of heat shock proteins on survival of isolated aortic cells from normal and atherosclerotic cynomolgus macaques. Atherosclerosis 84, 111–119.

    Article  CAS  PubMed  Google Scholar 

  • Johnson, J. D., Campisi, J., Sharkey, C. M., Kennedy, S. L., Nickerson, M. and Fleshner, M. (2005) Adrenergic receptors mediate stress-induced elevations in extracellular Hsp72. J Appl Physiol 99, 1789–1795.

    Article  CAS  PubMed  Google Scholar 

  • Johnson, A. D. and Tytell, M. (1993) Exogenous Hsp70 becomes cell associated, but not internalised by stressed arterial smooth muscle cells. In Vitro Cell Dev Biol 29A, 807–812.

    Article  CAS  Google Scholar 

  • Lancaster, G. I. and Febbraio, M. A. (2005a) Exosome-dependent trafficking of HSP70: a novel secretory pathway for cellular stress proteins. J Biol Chem 280, 23349–23355.

    Article  CAS  PubMed  Google Scholar 

  • Lancaster, G. I. and Febbraio, M. A. (2005b) Mechanisms of stress-induced cellular HSP72 release: implications for exercise-induced increases in extracellular HSP72. Exerc Immunol Rev 11, 46–52.

    PubMed  Google Scholar 

  • Lasunskaia, E. B., Fridlianskaia, I. I., Guzhova, I. V., Bozhkov, V. M. and Margulis, B. A. (1997) Accumulation of major stress protein 70 kDa protects myeloid and lymphoid cells from death by apoptosis. Apoptosis 2, 156–163.

    Article  CAS  PubMed  Google Scholar 

  • Lewthwaite, J., Owen, N., Coates, A., Henderson, B. and Steptoe, A. (2002) Circulating human heat shock protein 60 in the plasma of British civil servants. Circulation 106, 196–201.

    Article  CAS  PubMed  Google Scholar 

  • Liao, D. -F., Jin, Z. -G., Baas, A. S. et al. (2000) Purification and identification of secreted oxidative stress-induced factors from vascular smooth muscle cells. J Biol Chem 275, 189–196.

    Article  CAS  PubMed  Google Scholar 

  • Liu, A. Y., Lin, Z., Choi, H., Sorhage, F. and Li, B. (1989) Attenuated induction of heat shock gene expression in aging diploid fibroblasts. J Biol Chem 264, 12037–12045.

    CAS  PubMed  Google Scholar 

  • Luce, M. C. and Cristofalo, V. J. (1992) Reduction in heat shock gene expression correlates with increased thermosensitivity in senescent human fibroblasts. Exp Cell Res 202, 9–16.

    Article  CAS  PubMed  Google Scholar 

  • Mambula, S. S. and Calderwood, S. K. (2006) Heat shock protein 70 is secreted from tumor cells by a nonclassical pathway involving lysosomal endosomes. J Immunol 177, 7849–7857.

    CAS  PubMed  Google Scholar 

  • Martin-Ventura, J. L., Leclercq, A., Blanco-Colio, L. M. et al. (2007) Low plasma levels of HSP70 in patients with carotid atherosclerosis are associated with increased levels of proteolytic markers of neutrophil activation. Atherosclerosis 194, 334–341.

    Article  CAS  PubMed  Google Scholar 

  • Mosser, D. D., Caron, A. W., Bourget, L., Denis-Larose, C. and Massie, B. (1997) Role of the human heat shock protein hsp70 in protection against stress-induced apoptosis. Mol Cell Biol 17, 5317–5327.

    CAS  PubMed  Google Scholar 

  • Nitta, Y., Abe, K., Aoki, M., Ohno, I. and Isoyama, S. (1994) Diminished heat shock protein 70 mRNA induction in aged rats after ischemia. Am J Physiol 267, H1795–H1803.

    CAS  PubMed  Google Scholar 

  • Njemini, R., Lambert, M., Demanet, C. and Mets, T. (2003) Elevated serum heat-shock protein 70 levels in patients with acute infection: use of an optimized enzyme-linked immunosorbent assay. Scand J Immunol 58, 664–669.

    Article  CAS  PubMed  Google Scholar 

  • Pahlavani, M. A., Denny, M., Moore, S. A., Weindruch, R. and Richardson, A. (1995) The expression of heat shock protein 70 decreases with age in lymphocytes from rats and rhesus monkeys. Exp Cell Res 218, 310–318.

    Article  CAS  PubMed  Google Scholar 

  • Pockley, A. G., Bulmer, J., Hanks, B. M. and Wright, B. H. (1999) Identification of human heat shock protein 60 (Hsp60) and anti-Hsp60 antibodies in the peripheral circulation of normal individuals. Cell Stress Chaperones 4, 29–35.

    Article  CAS  PubMed  Google Scholar 

  • Pockley A. G, Calderwood S. K., Multhoff G. The atheroprotective properties of Hsp70: A role for Hsp70-endothelial interactions? Cell Stress & Chaperones, in press. DOI: 10.1007/s12192-009-0113-1.

    Google Scholar 

  • Pockley, A. G., de Faire, U., Kiessling, R., Lemne, C., Thulin, T. and Frostegård, J. (2002) Circulating heat shock protein and heat shock protein antibody levels in established hypertension. J Hypertension 20, 1815–1820.

    Article  CAS  Google Scholar 

  • Pockley, A. G., Georgiades, A., Thulin, T., de Faire, U. and Frostegård, J. (2003) Serum heat shock protein 70 levels predict the development of atherosclerosis in subjects with established hypertension. Hypertension 42, 235–238.

    Article  CAS  PubMed  Google Scholar 

  • Pockley, A. G., Shepherd, J. and Corton, J. (1998) Detection of heat shock protein 70 (Hsp70) and anti-Hsp70 antibodies in the serum of normal individuals. Immunol Invest 27, 367–377.

    Article  CAS  PubMed  Google Scholar 

  • Pockley, A. G., Wu, R., Lemne, C., Kiessling, R., de Faire, U. and Frostegård, J. (2000) Circulating heat shock protein 60 is associated with early cardiovascular disease. Hypertension 36, 303–307.

    CAS  PubMed  Google Scholar 

  • Rea, I. M., McNerlan, S. and Pockley, A. G. (2001) Serum heat shock protein and anti-heat shock protein antibody levels in aging. Exp Gerontology 36, 341–352.

    Article  CAS  Google Scholar 

  • Richardson, A. and Holbrook, N. J.. Aging and the cellular response to stress: reduction in the heat shock response. In: Cellular Aging and Cell Death, N. J. Holbrook, G. R. Martin, and R. A. Lockshin, eds. Wiley-Liss, New York, 1996, pp. 67–79.

    Google Scholar 

  • Ritossa, F. A. (1962) A new puffing pattern induced by temperature shock and DNP in Drosophila. Experientia 18, 571–573.

    Article  CAS  Google Scholar 

  • Robinson, M. B., Tidwell, J. L., Gould, T. et al. (2005) Extracellular heat shock protein 70: a critical component for motoneuron survival. J Neurosci 25, 9735–9745.

    Article  CAS  PubMed  Google Scholar 

  • Samali, A. and Cotter, T. G. (1996) Heat shock proteins increase resistance to apoptosis. Exp Cell Res 223, 163–170.

    Article  CAS  PubMed  Google Scholar 

  • Santoro, M. G. (2000) Heat shock factors and the control of the stress response. Biochem Pharmacol 59, 55–63.

    Article  CAS  PubMed  Google Scholar 

  • Shelton, D. N., Chang, E., Whittier, P. S., Choi, D. and Funk, W. D. (1999) Microarray analysis of replicative senescence. Cur Biol 9, 939–945.

    Article  CAS  Google Scholar 

  • Simon, M. M., Reikerstorfer, A., Schwarz, A. et al. (1995) Heat shock protein 70 overexpression affects the response to ultraviolet light in murine fibroblasts. Evidence for increased cell viability and suppression of cytokine release. J Clin Invest 95, 926–933.

    Article  CAS  PubMed  Google Scholar 

  • Terry, D. F., McCormick, M., Andersen, S. et al. (2004) Cardiovascular disease delay in centenarian offspring: role of heat shock proteins. Ann N Y Acad Sci 1019, 502–505.

    Article  CAS  PubMed  Google Scholar 

  • Thériault, J. R., Mambula, S. S., Sawamura, T., Stevenson, M. A. and Calderwood, S. K. (2005) Extracellular HSP70 binding to surface receptors present on antigen presenting cells and endothelial/epithelial cells. FEBS Lett 579, 1951–1960.

    Article  PubMed  Google Scholar 

  • Tidwell, J. L., Houenou, L. J. and Tytell, M. (2004) Administration of Hsp70 in vivo inhibits motor and sensory neuron degeneration. Cell Stress Chaperones 9, 88–98.

    CAS  PubMed  Google Scholar 

  • Tissières, A., Mitchell, H. K. and Tracy, U. (1974) Protein synthesis in salivary glands of Drosophila melanogaster: relation to chromosome puffs. J Mol Biol 84, 389–398.

    Article  PubMed  Google Scholar 

  • Tytell, M. (2005) Release of heat shock proteins (Hsps) and the effects of extracellular Hsps on neural cells and tissues. Int J Hyperthermia 21, 445–455.

    Article  CAS  PubMed  Google Scholar 

  • Tytell, M., Greenberg, S. G. and Lasek, R. J. (1986) Heat shock-like protein is transferred from glia to axon. Brain Res 363, 161–164.

    Article  CAS  PubMed  Google Scholar 

  • Walsh, R. C., Koukoulas, I., Garnham, A., Moseley, P. L., Hargreaves, M. and Febbraio, M. A. (2001) Exercise increases serum Hsp72 in humans. Cell Stress Chaperones 6, 386–393.

    Article  CAS  PubMed  Google Scholar 

  • Xu, Q., Schett, G., Perschinka, H. et al. (2000) Serum soluble heat shock protein 60 is elevated in subjects with atherosclerosis in a general population. Circulation 102, 14–20.

    CAS  PubMed  Google Scholar 

  • Zal, B., Kaski, J. C., Arno, G. et al. (2004) Heat-shock protein 60-reactive CD4+CD28null T cells in patients with acute coronary syndromes. Circulation 109, 1230–1235.

    Article  CAS  PubMed  Google Scholar 

  • Zhu, J., Quyyumi, A. A., Wu, H. et al. (2003) Increased serum levels of heat shock protein 70 are associated with low risk of coronary artery disease. Arterioscler Thromb Vasc Biol 23, 1055–1059.

    Article  CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Immunobiology Research Group, K Floor, The Medical School, University of Sheffield, Beech Hill Road, Sheffield, S10 2RX, UK

    Alan Graham Pockley

  2. Department of Radiotherapy and Radiooncology, Klinikum rechts der Isar, Technische Universität München, Munich, Germany

    Gabriele Multhoff

  3. Helmholtz Zentrum München, German Research Center for Environmental Health (GmbH), Clinical Cooperation Group ‘Innate Immunity in Tumor Biology’, Munich, Germany

    Gabriele Multhoff

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  1. Alan Graham Pockley
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Correspondence to Alan Graham Pockley .

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Editors and Affiliations

  1. College of Medicine, Texas A & M University System, South 1st St. 1901, Temple, 76508, U.S.A.

    Alexzander A. A. Asea

  2. Rigshospitalet, University of Copenhagen, Blegdamsvej 9, Koebenhavn, 2100, Denmark

    Bente K. Pedersen

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Pockley, A.G., Multhoff, G. (2010). Circulating HSP70 as an Endogenous Cytoprotector?. In: Asea, A., Pedersen, B. (eds) Heat Shock Proteins and Whole Body Physiology. Heat Shock Proteins, vol 5. Springer, Dordrecht. https://doi.org/10.1007/978-90-481-3381-9_18

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