Cell Stress and Chaperones

, Volume 22, Issue 2, pp 271–291 | Cite as

Acute exercise boosts cell proliferation and the heat shock response in lymphocytes: correlation with cytokine production and extracellular-to-intracellular HSP70 ratio

  • Thiago Gomes HeckEmail author
  • Sofia Pizzato Scomazzon
  • Patrícia Renck Nunes
  • Cinthia Maria Schöler
  • Gustavo Stumpf da Silva
  • Aline Bittencourt
  • Maria Cristina Faccioni-Heuser
  • Mauricio Krause
  • Roberto Barbosa Bazotte
  • Rui Curi
  • Paulo Ivo Homem de BittencourtJrEmail author
Original Paper


Exercise stimulates immune responses, but the appropriate “doses” for such achievements are unsettled. Conversely, in metabolic tissues, exercise improves the heat shock (HS) response, a universal cytoprotective response to proteostasis challenges that are centred on the expression of the 70-kDa family of intracellular heat shock proteins (iHSP70), which are anti-inflammatory. Concurrently, exercise triggers the export of HSP70 towards the extracellular milieu (eHSP70), where they work as pro-inflammatory cytokines. As the HS response is severely compromised in chronic degenerative diseases of inflammatory nature, we wondered whether acute exercise bouts of different intensities could alter the HS response of lymphocytes from secondary lymphoid organs and whether this would be related to immunoinflammatory responses. Adult male Wistar rats swam for 20 min at low, moderate, high or strenuous intensities as per an overload in tail base. Controls remained at rest under the same conditions. Afterwards, mesenteric lymph node lymphocytes were assessed for the potency of the HS response (42 °C for 2 h), NF-κB binding activity, mitogen-stimulated proliferation and cytokine production. Exercise stimulated cell proliferation in an “inverted-U” fashion peaking at moderate load, which was paralleled by suppression of NF-κB activation and nuclear location, and followed by enhanced HS response in relation to non-exercised animals. Comparative levels of eHSP70 to iHSP70 (H-index) matched IL-2/IL-10 ratios. We conclude that exercise, in a workload-dependent way, stimulates immunoinflammatory performance of lymphocytes of tissues far from the circulation and this is associated with H-index of stress response, which is useful to assess training status and immunosurveillance balance.


Heat shock response HSP70 eHSP70/iHSP70 ratio HSP70 H-index Exercise Lymphocyte Immune function Inflammation 





Antigen-presenting cell


Bovine serum albumin

Con A

Concanavalin A


3,3′-Diaminobenzidine tetrahydrochloride


4′,6-Diamidino-2-phenylindole dihydrochloride


Foetal bovine serum


Heat-induced epitope retrieval


Heat shock


Heat shock transcription factor-1


70 kDa family of heat shock proteins


Extracellular HSP70


Intracellular HSP70


Horseradish peroxidase


Immunoelectron microscopy






Inhibitor of nuclear factor κB (IκB) kinases




c-Jun N-terminal kinase


Nuclear transcription factors from the kappa light chain enhancer of activated B cells (κB) family


Peripheral blood mononuclear cells


Phosphate-buffered saline


Trichloroacetic acid


Toll-like receptor


Tumour necrosis factor-α



TGH and CMS were supported by a fellowship from CAPES-Brasília. SPS, PRN and GSS were supported by fellowships from CNPq. The authors are grateful to Sílvia Barbosa and Christiane Lopes for technical support in sample preparation for electronic microscopy. We also appreciate the free access to the facilities of The Federal University of Rio Grande do Sul Electronic Microscopy Centre (CME/UFRGS).

Author contribution

TGH and PIHBJ designed the study. TGH, SPS, PRN and AB completed all the experiments described in this manuscript. CMS and GSS performed experiments on gene expressions. MCFH, TGH and PIHBJ designed immunoelectron microscopy analyses and MCFH blindly analysed all the samples. All authors were involved in analysing the results. TGH, CMS and PIHB supervised statistical analyses. TGH, SPS, MK and PIHBJ co-wrote the paper. PIHBJ, MK, RBB and RC provided experimental advice and helped with manuscript revision. PIHB prepared the figures, performed microscopy quantifications and revised the final version of the manuscript. All the authors had final approval of the submitted and published versions.

Compliance with ethical standards

All the procedures performed in studies involving the animals followed the ethical rules established by Arouca’s Act (Federal Law 11794/2008) and the Guide for Care and Use of Experimental Animals published by the National Institutes of Health (NIH publication no. 85-23, revised in 1996). The procedures were approved by the Federal University of Rio Grande do Sul Ethics Committee on Animal Experimentation (CEUA #2008110), according to the guidelines of the Brazilian National Council for the Control of Animal Experimentation (CONCEA).


PIHBJ and RC were responsible for grant support with respect to The Brazilian National Council for Scientific and Technological Development [CNPq, grant #563870/2010-9 to RC and grants #5510987/2007-8, 402626/2012-5, 402364/2012-0 to PIHBJ], while TGH was responsible for grant support from CNPq [#382692/2011-0] and [FAPERGS no. 002106-2551/13-5] which funded the present work.

Conflict of interest

The authors declare that they have no conflicts of interest.

Supplementary material

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  1. Anckar J, Sistonen L (2011) Regulation of HSF1 function in the heat stress response: implications in aging and disease. Annu Rev Biochem 80:1089–1115. doi: 10.1146/annurev-biochem-060809-095203 PubMedCrossRefGoogle Scholar
  2. Asea A, Kraeft SK, Kurt-Jones EA, Stevenson MA, Chen LB, Finberg RW, Koo GC, Calderwood SK (2000) HSP70 stimulates cytokine production through a CD14-dependant pathway, demonstrating its dual role as a chaperone and cytokine. Nat Med 6(4):435–442. doi: 10.1038/74697 PubMedCrossRefGoogle Scholar
  3. Baker MA, Horvath SM (1964) Influence of water temperature on oxygen uptake by swimming rats. J Appl Physiol 19:1215–1218PubMedGoogle Scholar
  4. Baptista S, Piloto N, Reis F, Teixeira-de-Lemos E, Garrido AP, Dias A, Lourenço M, Palmeiro A, Ferrer-Antunes C, Teixeira F (2008) Treadmill running and swimming imposes distinct cardiovascular physiological adaptations in the rat: focus on serotonergic and sympathetic nervous systems modulation. Acta Physiol Hung 95(4):365–381. doi: 10.1556/APhysiol.2008.0002 PubMedCrossRefGoogle Scholar
  5. Belardo G, Piva R, Santoro MG (2010) Heat stress triggers apoptosis by impairing NF-κB survival signaling in malignant B cells. Leukemia 24(1):187–196. doi: 10.1038/leu.2009.227 PubMedCrossRefGoogle Scholar
  6. Boorstein WR, Ziegelhoffer T, Craig EA (1994) Molecular evolution of the HSP70 multigene family. J Mol Evol 38(1):1–17PubMedCrossRefGoogle Scholar
  7. Bradford MM (1976) A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem 72:248–254PubMedCrossRefGoogle Scholar
  8. Broquet AH, Thomas G, Masliah J, Trugnan G, Bachelet M (2003) Expression of the molecular chaperone Hsp70 in detergent-resistant microdomains correlates with its membrane delivery and release. J Biol Chem 278(24):21601–21206. doi: 10.1074/jbc.M302326200 PubMedCrossRefGoogle Scholar
  9. Brown ET, Umino Y, Loi T, Solessio E, Barlow R (2005) Anesthesia can cause sustained hyperglycemia in C57/BL6J mice. Vis Neurosci 22(5):615–618PubMedCrossRefGoogle Scholar
  10. Bruchim Y, Aroch I, Eliav A, Abbas A, Frank I, Kelmer E, Codner C, Segev G, Epstein Y, Horowitz M (2014) Two years of combined high-intensity physical training and heat acclimatization affect lymphocyte and serum HSP70 in purebred military working dogs. J Appl Physiol 117:112–118. doi: 10.1152/japplphysiol.00090.2014 PubMedCrossRefGoogle Scholar
  11. Calderwood SK, Theriault J, Gray PJ, Gong J (2007) Cell surface receptors for molecular chaperones. Methods 43(3):199–206PubMedCrossRefGoogle Scholar
  12. Campisi J, Fleshner M (2003) Role of extracellular HSP72 in acute stress-induced potentiation of innate immunity in active rats. J Appl Physiol 94(1):43–52PubMedCrossRefGoogle Scholar
  13. Chang Y, Chen TL, Sheu JR, Chen RM (2005) Suppressive effects of ketamine on macrophage functions. Toxicol Appl Pharmacol 204(1):27–35PubMedCrossRefGoogle Scholar
  14. Chirico WJ, Waters MG, Blobel G (1988) 70K heat shock related proteins stimulate protein translocation into microsomes. Nature 332(6167):805–810. doi: 10.1038/332805a0 PubMedCrossRefGoogle Scholar
  15. Chung J, Nguyen AK, Henstridge DC, Holmes AG, Chan MH, Mesa JL, Lancaster GI, Southgate RJ, Bruce CR, Duffy SJ, Horvath I, Mestril R, Watt MJ, Hooper PL, Kingwell BA, Vigh L, Hevener A, Febbraio MA (2008) HSP72 protects against obesity-induced insulin resistance. Proc Natl Acad Sci U S A 105(5):1739–1744PubMedPubMedCentralCrossRefGoogle Scholar
  16. Clayton A, Turkes A, Navabi H, Mason MD, Tabi Z (2005) Induction of heat shock proteins in B-cell exosomes. J Cell Sci 118(Pt 16):3631–3638PubMedCrossRefGoogle Scholar
  17. De Fries R, Mitsuhashi M (1995) Quantification of mitogen induced human lymphocyte proliferation: comparison of alamarBlue assay to 3H-thymidine incorporation assay. J Clin Lab Anal 9(2):89–95. doi: 10.1002/jcla.1860090203 PubMedCrossRefGoogle Scholar
  18. De Maio A (2011) Extracellular heat shock proteins, cellular export vesicles, and the stress observation system: a form of communication during injury, infection, and cell damage. It is never known how far a controversial finding will go! Dedicated to Ferruccio Ritossa Cell Stress Chaperones 16(3):235–249. doi: 10.1007/s12192-010-0236-4 PubMedCrossRefGoogle Scholar
  19. De Maio A, Vazquez D (2013) Extracellular heat shock proteins: a new location, a new function. Shock 40:239–246. doi: 10.1097/SHK.0b013e3182a185ab PubMedPubMedCentralCrossRefGoogle Scholar
  20. Demas GE, Zysling DA, Beechler BR, Muehlenbein MP, French SS (2011) Beyond phytohaemagglutinin: assessing vertebrate immune function across ecological contexts. J Anim Ecol 80(4):710–730. doi: 10.1111/j.1365-2656.2011.01813.x PubMedCrossRefGoogle Scholar
  21. Di Naso FC, Porto RR, Fillmann HS, Maggioni L, Padoin AV, Ramos RJ, Mottin CC, Bittencourt A, Marroni NA, Homem de Bittencourt PI Jr (2015) Obesity depresses the anti-inflammatory HSP70 pathway, contributing to NAFLD progression. Obesity 23(1):120–129. doi: 10.1002/oby.20919 PubMedCrossRefGoogle Scholar
  22. Dos Santos PC, Gehlen G, Faccioni-Heuser MC, Achaval M (2005) Detection of glial fibrillary acidic protein (GFAP) and vimentin (Vim) by immunoelectron microscopy of the glial cells in the central nervous system of the snail Megalobulimus abbreviatus. Acta Zool-Stockholm 86(2):135–144. doi: 10.1111/j.1463-6395.2005.00195.x CrossRefGoogle Scholar
  23. Drugan RC, Eren S, Hazi A, Silva J, Christianson JP, Kent S (2005) Impact of water temperature and stressor controllability on swim stress-induced changes in body temperature, serum corticosterone, and immobility in rats. Pharmacol Biochem Behav 82(2):397–403. doi: 10.1016/j.pbb.2005.09.011 PubMedCrossRefGoogle Scholar
  24. Eijsvogels TM, Thompson PD (2015) Exercise is medicine: at any dose? JAMA 314(18):1915–1916. doi: 10.1001/jama.2015.10858 PubMedCrossRefGoogle Scholar
  25. Febbraio MA, Pedersen BK (2005) Contraction-induced myokine production and release: is skeletal muscle an endocrine organ? Exerc Sport Sci Rev 33(3):114–119PubMedCrossRefGoogle Scholar
  26. Febbraio MA, Ott P, Nielsen HB, Steensberg A, Keller C, Krustrup P, Secher NH, Pedersen BK (2002) Exercise induces hepatosplanchnic release of heat shock protein 72 in humans. J Physiol 544(Pt 3):957–962PubMedPubMedCentralCrossRefGoogle Scholar
  27. Febbraio MA, Mesa JL, Chung J, Steensberg A, Keller C, Nielsen HB, Krustrup P, Ott P, Secher NH, Pedersen BK (2004) Glucose ingestion attenuates the exercise-induced increase in circulating heat shock protein. Cell Stress Chaperones 9:390–396PubMedPubMedCentralCrossRefGoogle Scholar
  28. Gelain DP, de Bittencourt Pasquali MA, Comic MC, Grunwald MS, Ritter C, Tomasi CD, Alves SC, Quevedo J, Dal-Pizzol F, Moreira JC (2011) Serum heat shock protein 70 levels, oxidant status, and mortality in sepsis. Shock 35(5):466–470. doi: 10.1097/SHK.0b013e31820fe704 PubMedCrossRefGoogle Scholar
  29. Genth-Zotz S, Bolger AP, Kalra PR, von Haehling S, Doehner W, Coats AJ, Volk HD, Anker SD (2004) Heat shock protein 70 in patients with chronic heart failure: relation to disease severity and survival. Int J Cardiol 96(3):397–401. doi: 10.1016/j.ijcard.2003.08.008 PubMedCrossRefGoogle Scholar
  30. Gibson OR, Dennis A, Parfitt T, Taylor L, Watt PW, Maxwell NS (2014) Extracellular Hsp72 concentration relates to a minimum endogenous criteria during acute exercise-heat exposure. Cell Stress Chaperones 19(3):389–400. doi: 10.1007/s12192-013-0468-1 PubMedCrossRefGoogle Scholar
  31. Giraldo J, Vivas NM, Vila E, Badia A (2002) Assessing the (a)symmetry of concentration-effect curves: empirical versus mechanistic models. Pharmacol Ther 95(1):21–45PubMedCrossRefGoogle Scholar
  32. Giraldo E, Multhoff G, Ortega E (2010) Noradrenaline increases the expression and release of Hsp72 by human neutrophils. Brain Behav Immun 24:672–677. doi: 10.1016/j.bbi.2010.02.003 PubMedCrossRefGoogle Scholar
  33. Gobatto CA, de Mello MA, Sibuya CY, de Azevedo JR, dos Santos LA, Kokubun E (2001) Maximal lactate steady state in rats submitted to swimming exercise. Comp Biochem Physiol A Mol Integr Physiol 130(1):21–27PubMedCrossRefGoogle Scholar
  34. Goettems-Fiorin PB, Salamoni B, Baldissera FG, Bender dos Santos A, Homem de Bittencourt PI Jr, Ludwig MS, Rhoden CR, Heck TG (2016) Fine particulate matter potentiates type 2 diabetes development in high-fat diet treated mice: stress response and extracellular to intracellular HSP70 ratio analysis. J Physiol Biochem 72(4):643–656. doi: 10.1007/s13105-016-0503-7 PubMedCrossRefGoogle Scholar
  35. Gottschalk PG, Dunn JR (2005) The five-parameter logistic: a characterization and comparison with the four-parameter logistic. Anal Biochem 343(1):54–65PubMedCrossRefGoogle Scholar
  36. Hackney AC (2006) Stress and the neuroendocrine system: the role of exercise as a stressor and modifier of stress. Expert Rev Endocrinol Metab 1(6):783–792. doi: 10.1586/17446651.1.6.783 PubMedPubMedCentralCrossRefGoogle Scholar
  37. Hageman J, van Waarde MA, Zylicz A, Walerych D, Kampinga HH (2011) The diverse members of the mammalian HSP70 machine show distinct chaperone-like activities. Biochem J 435(1):127–142. doi: 10.1042/BJ20101247 PubMedCrossRefGoogle Scholar
  38. Hanker JS (1979) Osmiophilic reagents in electronmicroscopic histocytochemistry. Prog Histochem Cytochem 12(1):1–85PubMedCrossRefGoogle Scholar
  39. Heck TG, Schöler CM, Homem de Bittencourt PI Jr (2011) HSP70 expression: does it a novel fatigue signalling factor from immune system to the brain? Cell Biochem Funct 29(3):215–226. doi: 10.1002/cbf.1739 PubMedCrossRefGoogle Scholar
  40. Henstridge DC, Febbraio MA, Hargreaves M (2016) Heat shock proteins and exercise adaptations. Our knowledge thus far and the road still ahead. J Appl Physiol 120(6):683–691. doi: 10.1152/japplphysiol.00811.2015 PubMedCrossRefGoogle Scholar
  41. Hightower LE, Guidon PT (1989) Selective release from cultured mammalian cells of heat-shock (stress) proteins that resemble glia-axon transfer proteins. J Cell Physiol 138:257–266. doi: 10.1002/jcp.1041380206 PubMedCrossRefGoogle Scholar
  42. Homem de Bittencourt PI Jr, Curi R (1998) Transfer of cholesterol from macrophages to lymphocytes in culture. Biochem Mol Biol Int 44(2):347–362. doi: 10.1080/15216549800201362 Google Scholar
  43. Homem de Bittencourt PI Jr, Peres CM, Yano MM, Hirata MH, Curi R (1993) Pyruvate is a lipid precursor for rat lymphocytes in culture: evidence for a lipid exporting capacity. Biochem Mol Biol Int 30(4):631–641PubMedGoogle Scholar
  44. Homem de Bittencourt PI Jr, Yano MM, Hirata MH, Williams JF, Curi R (1994) Evidence that prostaglandins modulate lipogenesis in cultured lymphocytes—a comparison with its effect on macrophages and tumour cells. Biochem Mol Biol Int 33(3):463–475Google Scholar
  45. Hooper PL, Balogh G, Rivas E, Kavanagh K, Vigh L (2014) The importance of the cellular stress response in the pathogenesis and treatment of type 2 diabetes. Cell Stress Chaperones 19(4):447–464. doi: 10.1007/s12192-014-0493-8 PubMedPubMedCentralCrossRefGoogle Scholar
  46. Horn P, Kalz A, Lim CL, Pyne D, Saunders P, Mackinnon L, Peake J, Suzuki K (2007) Exercise-recruited NK cells display exercise-associated eHSP-70. Exerc Immunol Rev 13:100–111PubMedGoogle Scholar
  47. Howarth KR, Phillips SM, MacDonald MJ, Richards D, Moreau NA, Gibala MJ (2010) Effect of glycogen availability on human skeletal muscle protein turnover during exercise and recovery. J Appl Physiol 109:431–438. doi: 10.1152/japplphysiol.00108.2009 PubMedCrossRefGoogle Scholar
  48. Hunter-Lavin C, Davies EL, Bacelar MM, Marshall MJ, Andrew SM, Williams JH (2004) Hsp70 release from peripheral blood mononuclear cells. Biochem Biophys Res Commun 324(2):511–517PubMedCrossRefGoogle Scholar
  49. Ireland HE, Leoni F, Altaie O, Birch CS, Coleman RC, Hunter-Lavin C, Williams JH (2007) Measuring the secretion of heat shock proteins from cells. Methods 43(3):176–183. doi: 10.1016/j.ymeth.2007.06.011 PubMedCrossRefGoogle Scholar
  50. Jenei ZM, Gombos T, Forhecz Z, Pozsonyi Z, Karadi I, Janoskuti L, Prohaszka Z (2013a) Elevated extracellular HSP70 (HSPA1A) level as an independent prognostic marker of mortality in patients with heart failure. Cell Stress Chaperones 18(6):809–813. doi: 10.1007/s12192-013-0425-z PubMedPubMedCentralCrossRefGoogle Scholar
  51. Jenei ZM, Szeplaki G, Merkely B, Karadi I, Zima E, Prohaszka Z (2013b) Persistently elevated extracellular HSP70 (HSPA1A) level as an independent prognostic marker in post-cardiac-arrest patients. Cell Stress Chaperones 18(4):447–454. doi: 10.1007/s12192-012-0399-2 PubMedPubMedCentralCrossRefGoogle Scholar
  52. Johnson JD, Fleshner M (2006) Releasing signals, secretory pathways, and immune function of endogenous extracellular heat shock protein 72. J Leukoc Biol 79(3):425–434PubMedCrossRefGoogle Scholar
  53. Johnson EM, Karn J, Allfrey VG (1974) Early nuclear events in the induction of lymphocyte proliferation by mitogens. Effects of concanavalin A on the phosphorylation and distribution of non-histone chromatin proteins. J Biol Chem 249(15):4990–4999PubMedGoogle Scholar
  54. Johnson JD, Campisi J, Sharkey CM, Kennedy SL, Nickerson M, Fleshner M (2005) Adrenergic receptors mediate stress-induced elevations in extracellular Hsp72. J Appl Physiol 99:1789–1795. doi: 10.1152/japplphysiol.00390.2005 PubMedCrossRefGoogle Scholar
  55. 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(1):105–111. doi: 10.1007/s12192-008-0068-7 PubMedCrossRefGoogle Scholar
  56. Kolberg A, Rosa TG, Puhl MT, Scola G, Janner DR, Lagranha DJ, Maslinkiewicz A, Heck TG, Curi R, Homem de Bittencourt PI Jr (2006) Low expression of MRP/GS-X pump ATPase in lymphocytes of Walker 256 tumor-bearing rats is associated with cyclopentenone prostaglandin accumulation and cancer immunodeficiency. Cell Biochem Funct 24(1):23–39. doi: 10.1002/cbf.1290 PubMedCrossRefGoogle Scholar
  57. Krause MS, Homem de Bittencourt PI Jr (2008) Type 1 diabetes: can exercise impair the autoimmune event? The L-arginine/glutamine coupling hypothesis. Cell Biochem Funct 26(4):406–433. doi: 10.1002/cbf.1470 CrossRefGoogle Scholar
  58. Krause MS, Rodrigues-Krause JC (2011) Extracellular heat shock proteins (eHSP70) in exercise: possible targets outside the immune system and their role for neurodegenerative disorders treatment. Med Hypotheses 76(2):286–290. doi: 10.1016/j.mehy.2010.10.025 PubMedCrossRefGoogle Scholar
  59. Krause MS, McClenaghan NH, Flatt PR, Homem de Bittencourt PI Jr, Murphy C, Newsholme P (2011) L-arginine is essential for pancreatic β-cell functional integrity, metabolism and defense from inflammatory challenge. J Endocrinol 211(1):87–97. doi: 10.1530/JOE-11-0236 PubMedCrossRefGoogle Scholar
  60. Krause MS, Keane K, Rodrigues-Krause JC, Crognale D, Egan B, De Vito G, Murphy C, Newsholme P (2014a) Elevated levels of extracellular heat-shock protein 72 (eHSP72) are positively correlated with insulin resistance in vivo and cause pancreatic β-cell dysfunction and death in vitro. Clin Sci 126(10):739–752. doi: 10.1042/CS20130678 PubMedCrossRefGoogle Scholar
  61. Krause M, Rodrigues-Krause J, O’Hagan C, Medlow P, Davison G, Susta D, Boreham C, Newsholme P, O’Donnell M, Murphy C, De Vito G (2014b) The effects of aerobic exercise training at two different intensities in obesity and type 2 diabetes: implications for oxidative stress, low-grade inflammation and nitric oxide production. Eur J Appl Physiol 114:251–260. doi: 10.1007/s00421-013-2769-6 PubMedCrossRefGoogle Scholar
  62. Krause MS, Bock PM, Takahashi HK, Homem de Bittencourt PI Jr, Newsholme P (2015a) The regulatory roles of NADPH oxidase, intra- and extra-cellular HSP70 in pancreatic islet function, dysfunction and diabetes. Clin Sci 128(11):789–803. doi: 10.1042/CS20140695 PubMedCrossRefGoogle Scholar
  63. Krause MS, Heck TG, Bittencourt A, Scomazzon SP, Newsholme P, Curi R, Homem de Bittencourt PI Jr (2015b) The chaperone balance hypothesis: the importance of the extracellular to intracellular HSP70 ratio (eHSP70/iHSP70) to inflammation-driven type 2 diabetes, the effect of exercise and the implications for clinical management. Mediat Inflamm 2015:249205. doi: 10.1155/2015/249205 CrossRefGoogle Scholar
  64. Kregel KC, Allen DL, Booth FW, Fleshner M, Henricksen E, Musch TI, O’Leary DS, Parks CM, Poole DC, Ra’anan AW, Sheriff DD, Sturek MS, Toth LA (2006) Resource book for the design of animal exercise protocols. American Physiological Society, Bethesda MD Accessed 1 Jan 2016Google Scholar
  65. Krenek S, Schlegel M, Berendonk TU (2013) Convergent evolution of heat-inducibility during subfunctionalization of the Hsp70 gene family. BMC Evol Biol 13:49. doi: 10.1186/1471-2148-13-49 PubMedPubMedCentralCrossRefGoogle Scholar
  66. Lacoste A, Malham SK, Cueff A, Poulet SA (2001) Noradrenaline modulates oyster hemocyte phagocytosis via a beta-adrenergic receptor-cAMP signaling pathway. Gen Comp Endocrinol 122:252–259. doi: 10.1006/gcen.2001.7643 PubMedCrossRefGoogle Scholar
  67. Lancaster GI, Febbraio MA (2005) Exosome-dependent trafficking of HSP70: a novel secretory pathway for cellular stress proteins. J Biol Chem 280(24):23349–23355PubMedCrossRefGoogle Scholar
  68. Leite JSM, Cruzat VF, Krause MS, Homem de Bittencourt PI Jr (2016) Physiological regulation of the heat shock response by glutamine: implications for chronic low-grade inflammatory diseases in age-related conditions. Nutrire 41:21. doi: 10.1186/s41110-016-0021-y CrossRefGoogle Scholar
  69. Lindquist S (1986) The heat-shock response. Annu Rev Biochem 55:1151–1191PubMedCrossRefGoogle Scholar
  70. Lindquist S, Craig EA (1988) The heat-shock proteins. Annu Rev Genet 22:631–677. doi: 10.1146/ PubMedCrossRefGoogle Scholar
  71. Locke M, Noble EG (1995) Stress proteins: the exercise response. Can J Appl Physiol 20(2):155–167PubMedCrossRefGoogle Scholar
  72. Lovell R, Madden L, Carroll S, McNaughton L (2007) The time-profile of the PBMC HSP70 response to in vitro heat shock appears temperature-dependent. Amino Acids 33(1):137–144PubMedCrossRefGoogle Scholar
  73. Ludwig MS, Minguetti-Câmara VC, Heck TG, Scomazzon SP, Nunes PR, Bazotte RB, Homem de Bittencourt PI Jr (2014) Short-term but not long-term hypoglycaemia enhances plasma levels and hepatic expression of HSP72 in insulin-treated rats: an effect associated with increased IL-6 levels but not with IL-10 or TNF-α. Mol Cell Biochem 397:97–107. doi: 10.1007/s11010-014-2176-2 PubMedCrossRefGoogle Scholar
  74. Mabry TR, Gold PE, McCarty R (1995) Age-related changes in plasma catecholamine responses to acute swim stress. Neurobiol Learn Mem 63(3):260–268PubMedCrossRefGoogle Scholar
  75. Madden J, Coward JC, Shearman CP, Grimble RF, Calder PC (2010) Hsp70 expression in monocytes from patients with peripheral arterial disease and healthy controls: monocyte Hsp70 in PAD. Cell Biol Toxicol 26(3):215–223. doi: 10.1007/s10565-009-9134-x PubMedCrossRefGoogle Scholar
  76. Magalhães FC, Amorim FT, Passos RL, Fonseca MA, Oliveira KP, Lima MR, Guimarães JB, Ferreira-Júnior JB, Martini AR, Lima NR, Soares DD, Oliveira EM, Rodrigues LO (2010) Heat and exercise acclimation increases intracellular levels of Hsp72 and inhibits exercise-induced increase in intracellular and plasma Hsp72 in humans. Cell Stress Chaperones 15:885–895. doi: 10.1007/s12192-010-0197-7
  77. Mambula SS, Stevenson MA, Ogawa K, Calderwood SK (2007) Mechanisms for Hsp70 secretion: crossing membranes without a leader. Methods 43(3):168–175PubMedPubMedCentralCrossRefGoogle Scholar
  78. Mastorakos G, Pavlatou M, Diamanti-Kandarakis E, Chrousos GP (2005) Exercise and the stress system. Hormones 4(2):73–89PubMedGoogle Scholar
  79. Matz JM, LaVoi KP, Blake MJ (1996) Adrenergic regulation of the heat shock response in brown adipose tissue. J Pharmacol Exp Ther 277(3):1751–1758PubMedGoogle Scholar
  80. Mayer MP, Bukau B (2005) Hsp70 chaperones: cellular functions and molecular mechanism. Cell Mol Life Sci 62(6):670–684. doi: 10.1007/s00018-004-4464-6 PubMedPubMedCentralCrossRefGoogle Scholar
  81. Miles J (2014) R squared, adjusted R squared. Wiley StatsRef: Statistics Reference Online, Hoboken. doi: 10.1002/9781118445112.stat06627 CrossRefGoogle Scholar
  82. Motulsky HM, Brown RE (2006) Detecting outliers when fitting data with nonlinear regression—a new method based on robust nonlinear regression and the false discovery rate. BMC Bioinformatics 7:123. doi: 10.1186/1471-2105-7-123 PubMedPubMedCentralCrossRefGoogle Scholar
  83. Newsholme P, Homem de Bittencourt PI Jr (2014) The fat cell senescence hypothesis: a mechanism responsible for abrogating the resolution of inflammation in chronic disease. Curr Opin Clin Nutr Metab Care 17(4):295–305. doi: 10.1097/MCO.0000000000000077 PubMedCrossRefGoogle Scholar
  84. Newsholme P, Homem de Bittencourt PI Jr, O’Hagan C, De Vito G, Murphy C, Krause MS (2009) Exercise and possible molecular mechanisms of protection from vascular disease and diabetes: the central role of ROS and nitric oxide. Clin Sci 118(5):341–349. doi: 10.1042/CS20090433 PubMedCrossRefGoogle Scholar
  85. Nieman DC (1997) Exercise immunology: practical applications. Int J Sports Med 18(Suppl 1):S91–100. doi: 10.1055/s-2007-972705 PubMedCrossRefGoogle Scholar
  86. Njemini R, Demanet C, Mets T (2004) Inflammatory status as an important determinant of heat shock protein 70 serum concentrations during aging. Biogerontology 5(1):31–38PubMedCrossRefGoogle Scholar
  87. Nunes RB, Heck TG, Alves JP, Dal Lago P (2015) Hemodynamic responses during an incremental swimming exercise test in rats. J Exerc Physiol Online 15(3):55–62 Accessed 13 Dec 2016Google Scholar
  88. Oehler R, Pusch E, Zellner M, Dungel P, Hergovics N, Homoncik M, Eliasen MM, Brabec M, Roth E (2001) Cell type-specific variations in the induction of hsp70 in human leukocytes by feverlike whole body hyperthermia. Cell Stress Chaperones 6(4):306–315PubMedPubMedCentralCrossRefGoogle Scholar
  89. Ogura Y, Naito H, Akin S, Ichinoseki-Sekine N, Kurosaka M, Kakigi R, Sugiura T, Powers SK, Katamoto S, Demirel HA (2008) Elevation of body temperature is an essential factor for exercise-increased extracellular heat shock protein 72 level in rat plasma. Am J Physiol Regul Integr Comp Physiol 294(5):R1600–R1607. doi: 10.1152/ajpregu.00581.2007 PubMedCrossRefGoogle Scholar
  90. Ortega E, Giraldo E, Hinchado MD, Martinez M, Ibanez S, Cidoncha A, Collazos ME, Garcia JJ (2006) Role of Hsp72 and norepinephrine in the moderate exercise-induced stimulation of neutrophils’ microbicide capacity. Eur J Appl Physiol 98(3):250–255PubMedCrossRefGoogle Scholar
  91. Ortega E, Hinchado MD, Martin-Cordero L, Asea A (2009) The effect of stress-inducible extracellular Hsp72 on human neutrophil chemotaxis: a role during acute intense exercise. Stress 12(3):240–249. doi: 10.1080/10253890802309853 PubMedCrossRefGoogle Scholar
  92. Press WH, Teukolsky SA, Vettering WT, Flannery BP (1988) Numerical recipes in C: the art of scientific computing. Cambridge University Press, New York, NYGoogle Scholar
  93. Ritossa F (1962) A new puffing pattern induced by temperature shock and DNP in Drosophila. Experientia 18:571–573. doi: 10.1007/BF02172188 CrossRefGoogle Scholar
  94. Rodrigues-Krause JC, Krause M, O’Hagan C, De Vito G, Boreham C, Murphy C, Newsholme P, Colleran G (2012) Divergence of intracellular and extracellular HSP72 in type 2 diabetes: does fat matter? Cell Stress Chaperones 17(3):293–302. doi: 10.1007/s12192-011-0319-x PubMedPubMedCentralCrossRefGoogle Scholar
  95. Rossato JS, Krause MS, Fernandes AJM, Fernandes JR, Seibt IL, Rech A, Homem de Bittencourt PI Jr (2014) Role of α- and β-adrenoreceptors in rat monocyte/macrophage function at rest and acute exercise. J Physiol Biochem 70(2):363–374. doi: 10.1007/s13105-013-0310-3 Google Scholar
  96. Rozera C, Carattoli A, De Marco A, Amici C, Giorgi C, Santoro MG (1996) Inhibition of HIV-1 replication by cyclopentenone prostaglandins in acutely infected human cells. Evidence for a transcriptional block. J Clin Invest 97(8):1795–1803. doi: 10.1172/JCI118609 PubMedPubMedCentralCrossRefGoogle Scholar
  97. Ruell PA, Simar D, Périard JD, Best S, Caillaud C, Thompson MW (2014) Plasma and lymphocyte Hsp72 responses to exercise in athletes with prior exertional heat illness. Amino Acids 46:1491–1499. doi: 10.1007/s00726-014-1721-3 PubMedCrossRefGoogle Scholar
  98. Saha JK, Xia J, Grondin JM, Engle SK, Jakubowski JA (2005) Acute hyperglycemia induced by ketamine/xylazine anesthesia in rats: mechanisms and implications for preclinical models. Exp Biol Med 230(10):777–784CrossRefGoogle Scholar
  99. Sandqvist A, Sistonen L (2004) Nuclear stress granules: the awakening of a sleeping beauty? J Cell Biol 164(1):15–17. doi: 10.1083/jcb.200311102 PubMedPubMedCentralCrossRefGoogle Scholar
  100. Scheller J, Chalaris A, Schmidt-Arras D, Rose-John S (2011) The pro- and anti-inflammatory properties of the cytokine interleukin-6. Biochim Biophys Acta 1813:878–888. doi: 10.1016/j.bbamcr.2011.01.034 PubMedCrossRefGoogle Scholar
  101. Schöler CM, Marques CV, da Silva GS, Heck TG, de Oliveira Junior LP, Homem de Bittencourt PI Jr (2016) Modulation of rat monocyte/macrophage innate functions by increasing intensities of swimming exercise is associated with heat shock protein status. Mol Cell Biochem 421:111–125. doi: 10.1007/s11010-016-2791-1 PubMedCrossRefGoogle Scholar
  102. Smith RM, Charron MJ, Shah N, Lodish HF, Jarett L (1991) Immunoelectron microscopic demonstration of insulin-stimulated translocation of glucose transporters to the plasma membrane of isolated rat adipocytes and masking of the carboxyl-terminal epitope of intracellular GLUT4. Proc Natl Acad Sci U S A 88(15):6893–6897PubMedPubMedCentralCrossRefGoogle Scholar
  103. Speaker KJ, Cox SS, Paton MM, Serebrakian A, Maslanik T, Greenwood BN, Fleshner M (2014) Six weeks of voluntary wheel running modulates inflammatory protein (MCP-1, IL-6, and IL-10) and DAMP (Hsp72) responses to acute stress in white adipose tissue of lean rats. Brain Behav Immun 39:87–98. doi: 10.1016/j.bbi.2013.10.028 PubMedCrossRefGoogle Scholar
  104. Terry DF, McCormick M, Andersen S, Pennington J, Schoenhofen E, Palaima E, Bausero M, Ogawa K, Perls TT, Asea A (2004) Cardiovascular disease delay in centenarian offspring: role of heat shock proteins. Ann N Y Acad Sci 1019:502–505PubMedPubMedCentralCrossRefGoogle Scholar
  105. Terry DF, Wyszynski DF, Nolan VG, Atzmon G, Schoenhofen EA, Pennington JY, Andersen SL, Wilcox MA, Farrer LA, Barzilai N, Baldwin CT, Asea A (2006) Serum heat shock protein 70 level as a biomarker of exceptional longevity. Mech Ageing Dev 127(11):862–868PubMedPubMedCentralCrossRefGoogle Scholar
  106. Török Z, Crul T, Maresca B, Schütz GJ, Viana F, Dindia L, Piotto S, Brameshuber M, Balogh G, Péter M, Porta A, Trapani A, Gombos I, Glatz A, Gungor B, Peksel B, Vigh L Jr, Csoboz B, Horváth I, Vijayan MM, Hooper PL, Harwood JL, Vigh L (2014) Plasma membranes as heat stress sensors: from lipid-controlled molecular switches to therapeutic applications. Biochim Biophys Acta 1838(6):1594–1618. doi: 10.1016/j.bbamem.2013.12.015 PubMedCrossRefGoogle Scholar
  107. Van Handel E (1965) Estimation of glycogen in small amounts of tissue. Anal Biochem 11(2):256–265. doi: 10.1016/0003-2697(65)90013-8 PubMedCrossRefGoogle Scholar
  108. Vega VL, Rodríguez-Silva M, Frey T, Gehrmann M, Diaz JC, Steinem C, Multhoff G, Arispe N, De Maio A (2008) Hsp70 translocates into the plasma membrane after stress and is released into the extracellular environment in a membrane-associated form that activates macrophages. J Immunol 180(6):4299–4307. doi: 10.4049/jimmunol.180.6.4299 PubMedCrossRefGoogle Scholar
  109. Verghese J, Abrams J, Wang Y, Morano KA (2012) Biology of the heat shock response and protein chaperones: budding yeast (Saccharomyces cerevisiae) as a model system. Microbiol Mol Biol Rev 76(2):115–158. doi: 10.1128/MMBR.05018-11 PubMedPubMedCentralCrossRefGoogle Scholar
  110. Vieira R, Nascimento R, Arizawa S, Curi R (1990) Development of equipments for lymphocytes isolation and culture. Braz Arch Biol Technol 33:819–829Google Scholar
  111. Vitorino DC, Buzzachera CF, Curi R, Fernandes LC (2010) Effect of chronic supplementation with shark liver oil on immune responses of exercise-trained rats. Eur J Appl Physiol 108(6):1225–1232. doi: 10.1007/s00421-009-1267-3 PubMedCrossRefGoogle Scholar
  112. Voltarelli FA, Gobatto CA, de Mello MA (2002) Determination of anaerobic threshold in rats using the lactate minimum test. Braz J Med Biol Res 35(11):1389–1394. doi: 10.1590/S0100-879X2002001100018 PubMedCrossRefGoogle Scholar
  113. Walsh RC, Koukoulas I, Garnham A, Moseley PL, Hargreaves M, Febbraio MA (2001) Exercise increases serum Hsp72 in humans. Cell Stress Chaperones 6(4):386–393PubMedPubMedCentralCrossRefGoogle Scholar
  114. Walsh NP, Gleeson M, Shephard RJ, Gleeson M, Woods JA, Bishop NC, Fleshner M, Green C, Pedersen BK, Hoffman-Goetz L, Rogers CJ, Northoff H, Abbasi A, Simon P (2011a) Position statement. Part one: immune function and exercise. Exerc Immunol Rev 17:6–63PubMedGoogle Scholar
  115. Walsh NP, Gleeson M, Pyne DB, Nieman DC, Dhabhar FS, Shephard RJ, Oliver SJ, Bermon S, Kajeniene A (2011b) Position statement. Part two: maintaining immune health. Exerc Immunol Rev 17:64–103PubMedGoogle Scholar
  116. Whitham M, Fortes MB (2008) Heat shock protein 72: release and biological significance during exercise. Front Biosci 13:1328–1339. doi: 10.2741/2765 PubMedCrossRefGoogle Scholar
  117. Whitham M, Walker GJ, Bishop NC (2006) Effect of caffeine supplementation on the extracellular heat shock protein 72 response to exercise. J Appl Physiol 101(4):1222–1227PubMedCrossRefGoogle Scholar
  118. Yamada PM, Amorim FT, Moseley P, Robergs R, Schneider SM (2007) Effect of heat acclimation on heat shock protein 72 and interleukin-10 in humans. J Appl Physiol 103:1196–1204PubMedCrossRefGoogle Scholar
  119. Yang X, Zheng J, Bai Y, Tian F, Yuan J, Sun J, Liang H, Guo L, Tan H, Chen W, Tanguay RM, Wu T (2007) Using lymphocyte and plasma Hsp70 as biomarkers for assessing coke oven exposure among steel workers. Environ Health Perspect 115:1573–1577PubMedPubMedCentralCrossRefGoogle Scholar
  120. Ye J, Zhu R, He X, Feng Y, Yang L, Zhu X, Deng Q, Wu T, Zhang X (2014) Association of plasma IL-6 and Hsp70 with HRV at different levels of PAHs metabolites. PLoS One 9(4):e92964. doi: 10.1371/journal.pone.0092964 PubMedPubMedCentralCrossRefGoogle Scholar

Copyright information

© Cell Stress Society International 2017

Authors and Affiliations

  • Thiago Gomes Heck
    • 1
    • 2
    Email author
  • Sofia Pizzato Scomazzon
    • 2
    • 3
  • Patrícia Renck Nunes
    • 2
  • Cinthia Maria Schöler
    • 2
  • Gustavo Stumpf da Silva
    • 2
  • Aline Bittencourt
    • 2
  • Maria Cristina Faccioni-Heuser
    • 4
  • Mauricio Krause
    • 2
  • Roberto Barbosa Bazotte
    • 5
  • Rui Curi
    • 6
    • 7
  • Paulo Ivo Homem de BittencourtJr
    • 2
    Email author
  1. 1.Physiology Research Group, Department of Life Sciences, Postgraduate Program in Integral Attention to HealthRegional University of the Northwestern Rio Grande do Sul StateIjuíBrazil
  2. 2.Laboratory of Cellular Physiology, Department of Physiology, Institute of Basic Health SciencesFederal University of Rio Grande do SulPorto AlegreBrazil
  3. 3.Department of BiologyUniversity of Rome Tor VergataRomeItaly
  4. 4.Department of Morphological Sciences, Institute of Basic Health SciencesFederal University of Rio Grande do SulPorto AlegreBrazil
  5. 5.Department of Pharmacology and TherapeuticsState University of MaringáMaringáBrazil
  6. 6.Department of Physiology and Biophysics, Institute of Biomedical SciencesUniversity of São PauloSão PauloBrazil
  7. 7.Institute of Physical Activity Sciences and SportsCruzeiro do Sul UniversitySão PauloBrazil

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