Download PDF
Int J Sports Med 2013; 34(06): 559-564
DOI: 10.1055/s-0032-1327650
Immunology
© Georg Thieme Verlag KG Stuttgart · New York

Effects of Habitual Exercise on the eHsp72-Induced Release of Inflammatory Cytokines by Macrophages from Obese Zucker Rats

J. J. Garcia
1   Physiology, University of Extremadura, Badajoz, Spain
,
L. Martin-Cordero
1   Physiology, University of Extremadura, Badajoz, Spain
,
M. D. Hinchado
1   Physiology, University of Extremadura, Badajoz, Spain
,
M. E. Bote
1   Physiology, University of Extremadura, Badajoz, Spain
,
E. Ortega
1   Physiology, University of Extremadura, Badajoz, Spain
› Author Affiliations
Further Information

Publication History



accepted after revision 04 September 2012

Publication Date:
23 November 2012 (online)

Also available at
    Permissions and Reprints

Abstract

Regular exercise is a good non-pharmacological treatment of metabolic syndrome in that it improves obesity, diabetes, and inflammation. The 72 kDa extracellular heat shock protein (eHsp72) is released during exercise, thus stimulating the inflammatory responses. The aim of the present work was to evaluate the effect of regular exercise on the eHsp72-induced release of IL-1β, IL-6, and TNFα by macrophages from genetically obese Zucker rats (fa/fa) (ObZ), using lean Zucker (LZ) rats (Fa/fa) to provide reference values. ObZ presented a higher plasma concentration of eHsp72 than LZ, and exercise increased that concentration. In response to eHsp72, the macrophages from ObZ released less IL-1β and TNFα, but more IL-6, than macrophages from LZ. While eHsp72 stimulated the release of IL-1β, TNFα, and IL-6 in the macrophages from healthy LZ (with respect to the constitutive release), it inhibited the release of IL-1β and IL-6 in macrophages from ObZ. The habitual exercise improved the release of inflammatory cytokines by macrophages from ObZ in response to eHsp72 (it increased IL-1β and TNFα, and decreased IL-6), tending to values closer to those determined in healthy LZ. A deregulated macrophage inflammatory and stress response induced by eHsp72 underlies MS, and this is improved by habitual exercise.

Key words

obesity - inflammation - IL-1β - IL-6 - TNFα - Zucker rats
 

  • References

  • 1 Asea A. Stress proteins and initiation of immune response: chaperokine activity of hsp72. Exerc Immunol Rev 2005; 11: 34-45
    PubMedGoogle Scholar
  • 2 Asea A, Kraeft SK, Kurt-Jones EA, Stevenson MA, Chen LB, Finberg RW, Koo GC, Calderwood SK. HSP70 stimulates cytokine production through a CD14-dependant pathway, demonstrating its dual role as a chaperone and cytokine. Nat Med 2000; 6: 435-442
    CrossrefPubMedGoogle Scholar
  • 3 Barriga C, Martín MI, Ortega E, Rodriguez AB. Physiological concentrations of melatonin and corticosterone in stress and their relationship with phagocytic activity. J Neuroendocrinol 2002; 14: 691-695
    CrossrefPubMedGoogle Scholar
  • 4 Bassuk SS, Manson JE. Epidemiological evidence for the role of physical activity in reducing risk of type 2 diabetes and cardiovascular disease. J Appl Physiol 2005; 99: 1193-1204
    CrossrefPubMedGoogle Scholar
  • 5 Bray GA. Complications of obesity. Ann Int Med 1985; 103: 1052-1062
    CrossrefPubMedGoogle Scholar
  • 6 Campisi J, Leem TH, Fleshner M. Stress-induced extracellular Hsp72 is a functionally significant danger signal to the immune system. Cell Stress Chaperones 2003; 8: 272-286
    CrossrefPubMedGoogle Scholar
  • 7 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. Hsp72 protects against obesity-induced insulin resistance. Proc Natl Acad Sci USA 2008; 105: 1739-1744
    CrossrefPubMedGoogle Scholar
  • 8 Das UN. Is metabolic syndrome X an inflammatory condition?. Exp Biol Med 2002; 227: 989-997
    PubMedGoogle Scholar
  • 9 De Lemos ET, Reis F, Baptista S, Pinto R, Sepodes B, Vala H, Rocha-Pereira P, Silva AS, Teixeira F. Exercise training is associated with improved levels of C-reactive protein and adiponectin in ZDF (type 2) diabetic rats. Med Sci Monit 2007; 13: 168-174
    PubMedGoogle Scholar
  • 10 Eckel RH, Grundy SM, Zimmet PZ. The metabolic syndrome. Lancet 2005; 365: 1415-1428
    CrossrefPubMedGoogle Scholar
  • 11 Elenkov IJ, Chrousos GP. Stress hormones, pro-inflammatory and anti-inflammatory cytokines, and autoimmunity. Ann NY Acad Sci 2002; 966: 290-303
    CrossrefPubMedGoogle Scholar
  • 12 Fehrenbach E, Niess AM, Voelker K, Northoff H, Mooren FC. Exercise intensity and duration affect blood soluble HSP72. Int J Sports Med 2005; 26: 552-557
    Article in Thieme ConnectPubMedGoogle Scholar
  • 13 Ferrandez MD, de la Fuente M, Fernandez E, Manso R. Anabolic steroids and lymphocyte function in sedentary and exercise-trained rats. J Steroid Biochem Mol Biol 1996; 59: 225-232
    CrossrefPubMedGoogle Scholar
  • 14 Fleshner M, Campisi J, Amiri L, Diamond DM. Cat exposure induces both intra- and extracellular Hsp72: the role of adrenal hormones. Psychoneuroendocrinology 2004; 29: 1142-1152
    CrossrefPubMedGoogle Scholar
  • 15 Fleshner M, Campisi J, Johnson JD. Can exercise stress facilitate innate immunity? A functional role for stress-induced extracellular Hsp72. Exerc Immunol Rev 2003; 9: 6-24
    PubMedGoogle Scholar
  • 16 Giraldo E, Garcia JJ, Hinchado MD, Ortega E. Exercise intensity-dependent changes in the inflammatory response in sedentary women: role of neuroendocrine parameters in the neutrophil phagocytic process and the pro-/anti-inflammatory cytokine balance. Neuroimmunomodulation 2009; 16: 237-244
    CrossrefPubMedGoogle Scholar
  • 17 Giraldo E, Martín-Cordero M, García JJ, Gehrmann M, Multhoff G, Ortega E. Exercise-induced extracellular 72 kDa heat shock protein (Hsp72) stimulates neutrophil phagocytic and fungicidal capacities via TLR-2. Eur J Appl Physiol 2010; 108: 217-225
    CrossrefPubMedGoogle Scholar
  • 18 Giraldo E, Multhoff G, Ortega E. Noradrenaline increases the expression and release of Hsp72 by human neutrophils. Brain Behav Immun 2010; 24: 672-677
    CrossrefPubMedGoogle Scholar
  • 19 Harriss DJ, Atkinson G. Update – ethical standards in sport and exercise science research. Int J Sports Med 2011; 32: 819-821
    Article in Thieme ConnectPubMedGoogle Scholar
  • 20 Hotamisligil GS. Inflammation and metabolic disorders. Nature 2006; 444: 860-867
    CrossrefPubMedGoogle Scholar
  • 21 Hotamisligil GS, Shargill NS, Spiegelman BM. Adipose expression of tumor necrosis factor-alpha: direct role in obesity-linked insulin resistance. Science 1993; 259: 87-91
    CrossrefPubMedGoogle Scholar
  • 22 Johnson JD, Fleshner M. Releasing signals, secretory pathways, and immune function of endogenous extracellular heat shock protein 72. J Leukoc Biol 2006; 79: 425-434
    CrossrefPubMedGoogle Scholar
  • 23 Kaur P, Reis MD, Couchman GR, Forjuoh SN, Greene JF, Asea A. Role of heat shock proteins in obesity and type 2 diabetes. In: Asea A, Pedersen BK. (eds.). Heat Shock Proteins and Whole Body Physiology. Springer; 2010: 19-29
    CrossrefGoogle Scholar
  • 24 Kawanishi N, Yano H, Yokogawa Y, Suzuki K. Exercise training inhibits inflammation in adipose tissue via both suppression of macrophage infiltration and acceleration of phenotypic switching from M1 to M2 macrophages in high-fat-diet-induced obese mice. Exerc Immunol Rev 2010; 16: 105-118
    PubMedGoogle Scholar
  • 25 Knight RJ, Bodian C, Rodriguez-Laiz G, Guy SR, Fishbein TM. Risk factors for intra-abdominal infection after pancreas transplantation. Am J Surg 2000; 179: 99-102
    CrossrefPubMedGoogle Scholar
  • 26 Lindquist S, Craig EA. The heat shock proteins. Annu Rev Genet 1988; 22: 631-677
    CrossrefPubMedGoogle Scholar
  • 27 Martin-Cordero L, Garcia JJ, Giraldo E, De la Fuente M, Manso R, Ortega E. Influence of exercise on the circulating levels and macrophage production of IL-1beta and IFNgamma affected by metabolic syndrome: an obese Zucker rat experimental animal model. Eur J Appl Physiol 2009; 107: 535-543
    CrossrefPubMedGoogle Scholar
  • 28 Martín-Cordero L, García JJ, Hinchado MD, Bote E, Manso R, Ortega E. Habitual physical exercise improves macrophage IL-6 and TNF-α deregulated release in the obese Zucker rat model of the metabolic syndrome. Neuroimmunomodulation 2011; 18: 123-130
    CrossrefPubMedGoogle Scholar
  • 29 Martín-Cordero L, García JJ, Hinchado MD, Ortega E. The interleukin-6 and noradrenaline mediated inflammation-stress feedback mechanism is dysregulated in metabolic syndrome: effect of exercise. Cardiovasc Diabetol 2011; 10: 42
    CrossrefPubMedGoogle Scholar
  • 30 Matzinger P. Tolerance, danger and the extended family. Annu Rev Immunol 1994; 12: 991-1045
    CrossrefPubMedGoogle Scholar
  • 31 Matzinger P. An innate sense of danger. Semin Immunol 1998; 10: 399-415
    CrossrefPubMedGoogle Scholar
  • 32 Moran M, Delgado J, González B, Manso R, Megias A.. Responses of rat myocardial antioxidant defences and heat shock protein Hsp72 induced by 12- and 24-week treadmill training. Acta Physiol Scand 2004; 180: 157-166
    CrossrefPubMedGoogle Scholar
  • 33 Moseley PL. Heat shock proteins and the inflammatory response. Ann NY Acad Sci 1998; 856: 206-213
    CrossrefPubMedGoogle Scholar
  • 34 Ortega E. Neuroendocrine mediators in the modulation of phagocytosis by exercise: physiological implications. Exerc Immunol Rev 2003; 9: 70-94
    PubMedGoogle Scholar
  • 35 Ortega Rincón E. Physiology and biochemistry: influence of exercise on phagocytosis. Int J Sports Med 1994; 15: 172-178
    Article in Thieme ConnectPubMedGoogle Scholar
  • 36 Ortega E, Forner MA, Barriga C. Effect of beta-endorphin on adherence, chemotaxis, and phagocytosis of Candida albicans by peritoneal macrophages. Comp Immunol Microbiol Infect Dis 1996; 19: 267-274
    CrossrefPubMedGoogle Scholar
  • 37 Ortega E, García JJ, Bote ME, Martin-Cordero L, Escalante Y, Saavedra JM, Northoff H, Giraldo E. Exercise in fibromyalgia and related inflammatory disorders: known effects and unknown chances. Exerc Immunol Rev 2009; 15: 42-65
    PubMedGoogle Scholar
  • 38 Ortega E, García JJ, De la Fuente M. Ageing modulates some aspects of the non-specific immune response of murine macrophages and lymphocytes. Exp Physiol 2000; 85: 519-525
    CrossrefPubMedGoogle Scholar
  • 39 Ortega E, García JJ, Sáez MC, De la Fuente M. Changes with aging in the modulation of macrophage by norepinephrine. Mech Ageing Dev 2000; 118: 103-114
    CrossrefPubMedGoogle Scholar
  • 40 Ortega E, Giraldo E, Hinchado MD, Martín L, García JJ, De la Fuente M. Neuroimmunomodulation during exercise: role of catecholamines as “stress mediator” and/or danger signal for the innate immune response. Neuroimmunomodulation 2007; 14: 206-212
    CrossrefPubMedGoogle Scholar
  • 41 Ortega E, Giraldo E, Hinchado MD, Martín-Cordero L, García JJ. 72 kDa extracellular heat shock protein (eHsp72), norepinephrine (NE), and the innate immune response following moderate exercise. In: Asea A, Pedersen BK. (eds.). Heat Shock Proteins and Whole Body Physiology. Springer; 2010: 329-350
    CrossrefGoogle Scholar
  • 42 Ortega E, Giraldo E, Hinchado MD, Martínez M, Ibáñez S, Cidoncha A, Collazos ME, García JJ. Role of Hsp72 and norepinephrine in the moderate exercise-induced stimulation of neutrophils’ microbicide capacity. Eur J Appl Physiol 2006; 98: 250-255
    CrossrefPubMedGoogle Scholar
  • 43 Ortega E, Hinchado MD, Martín-Cordero L, Asea A. The effect of stress-inducible extracelular Hsp72 on human neutrophils chemotaxis: the role during acute intense exercise. Stress 2009; 12: 240-249
    CrossrefPubMedGoogle Scholar
  • 44 Ortega E, Rodríguez MJ, Barriga C, Forner MA. Corticosterone, prolactin, and thyroid hormones as hormonal mediators of the stimulated phagocytic capacity of peritoneal macrophages after high-intensity exercise. Int J Sports Med 1996; 17: 149-155
    Article in Thieme ConnectPubMedGoogle Scholar
  • 45 Pedersen BK. The anti-inflammatory effect of exercise: its role in diabetes and cardiovascular disease control. Essays Biochem 2006; 42: 105-117
    CrossrefPubMedGoogle Scholar
  • 46 Petersen AM, Pedersen BK. The anti-inflammatory effect of exercise. J Appl Physiol 2005; 98: 1154-1162
    CrossrefPubMedGoogle Scholar
  • 47 Plotkin BJ, Paulson D, Chelich A, Jurak D, Cole J, Kasimos J, Burdick JR, Casteel N. Immune responsiveness in a rat model for type II diabetes (Zucker rat, fa/fa): susceptibility to Candida albicans infection and leucocyte function. J Med Microbiol 1996; 44: 277-283
    CrossrefPubMedGoogle Scholar
  • 48 Teixeira-Lemos E, Nunes S, Texeira F, Reis F. Regular physical exercise training assists in preventing type 2 diabetes development: focus on its antioxidant and anti-inflammatory properties. Cardiovasc Diabetol 2011; 10: 12
    CrossrefPubMedGoogle Scholar
  • 49 Teixeira de Lemos E, Reis F, Baptista S, Pinto R, Sepodes B, Vala H, Rocha-Pereira P, Correia da Sisva G, Teixeira N, Silva AS, Carvalho L, Texeira F, Das UN. Exercise training decreases proinflammatory profile in Zucker diabetic (type 2) fatty rats. Nutrition 2009; 25: 330-339
    CrossrefPubMedGoogle Scholar
  • 50 Walsh RC, Koukolas I, Garnham A, Moseley PL, Hargreaves M, Febbraio MA. Exercise increases serum Hsp72 in humans. Cell Stress Chaperones 2001; 6: 386-393
    CrossrefPubMedGoogle Scholar
  • 51 Wellen KE, Hotamisligil GS. Inflammation, stress, and diabetes. J Clin Invest 2005; 115: 1111-1119
    Google Scholar
  • 52 Whitham M, Febbraio MA. HSP and diabetes. In: Asea A, Pedersen BK. (eds.). Heat Shock Proteins and Whole Body Physiology. Springer; 2010: 3-18
    CrossrefGoogle Scholar