The “bioregulatory effect of exercise” on the innate/inflammatory responses


The effects of exercise on the innate response are primarily mediated by the SNS (sympathetic nervous system) and/or the HPA (hypothalamic-pituitary-adrenal) axis and by stress proteins such as Hsp72. Regular exercise can induce immuno-neuroendocrine stabilization in persons with deregulated inflammatory and stress feedback by reducing the presence of stress hormones and inflammatory cytokines. Anti-inflammatory and “anti-stress” responses seem also to be induced (paradoxically, opposite to the effects in healthy persons) after sessions of exercise, being a promising strategy for treating certain inflammatory pathologies. Nevertheless, the biomedical side effects of exercise are also needed to be considered. This article defines the “Bioregulatory Effect of Exercise” to be one that reduces or prevents any excessive effect of inflammatory mediators and stimulates (or at least does not impair) the innate defences (i.e. chemotaxis, phagocytosis, and microbicidal activities) against pathogens. It also generates immunophysiological adaptations through an optimal balance between the pro- and the anti-inflammatory responses. These effects are mediated via immuno-neuroendocrine interactions. This review analyses concepts and conclusions related to how exercise affects the innate and/or inflammatory responses and discusses some paradoxical interpretations relevant for the practical use of exercise in treating infectious and inflammatory diseases. A potential role of exercise as hormesis strategy and the concept of exercise immunization are also discussed.

This is a preview of subscription content, log in to check access.

Fig. 1


  1. 1.

    Besedovsky HO, Del Rey A (2007) Physiology of psychoneuroimmunology: a personal view. Brain Behav Immun 21:34–44

    CAS  Article  PubMed  Google Scholar 

  2. 2.

    Bote ME, García JJ, Hinchado MD, Ortega E (2012) Inflammatory/stress feedback dysregulation in women with fibromyalgia. Neuroimmunomodulation 19:343–351

    CAS  Article  PubMed  Google Scholar 

  3. 3.

    Bote ME, García JJ, Hinchado MD, Ortega E (2013) Fibromyalgia: anti-inflammatory and stress responses after acute moderate exercise. Plos One 8(9):e74524

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  4. 4.

    Bote ME, García JJ, Hinchado MD, Ortega E (2014) An exploratory study of the effect of regular aquatic exercise on the function of neutrophils from women with fibromyalgia: role of IL-8 and noradrenaline. Brain Behav Immun 51:576–581

    Google Scholar 

  5. 5.

    Bote ME, Ortega E (2015) Regulation by exercise of the altered inflammatory status: response in fibromyalgia patients. Arch Med Deporte 32:136–143

    Google Scholar 

  6. 6.

    Bruunsgaard H, Pedersen BK (2003) Age-related inflammatory cytokines and disease. Immunol Allergy Clin North Am 23:15–59

    Article  PubMed  Google Scholar 

  7. 7.

    Calabrese EJ (2002) Hormesis: changing view of the dose-response, a personal account of the history and current status. Mutat Res 511:181–189

    CAS  Article  PubMed  Google Scholar 

  8. 8.

    Calabrese EJ, Baldwin LA (1998) Hormesis as a biological hypothesis. Enviromental Health Perspectives 106:357–362

    Article  Google Scholar 

  9. 9.

    Cooper DA, Radom-Aizik S, Schwindt C, Zaldivar F Jr (2007) Dangerous exercise: lessons learned from dysregulated inflammatory responses to physical activity. J Appl Physiol 103:700–709

    CAS  Article  PubMed  Google Scholar 

  10. 10.

    De la Fuente M, Cruces J, Hernandez O, Ortega E (2011) Strategies to improve the functions and redox state of the immune system in aged subjects. Curr Phama Des 17:3966–3993

    Article  Google Scholar 

  11. 11.

    De la Fuente M, Miquel J (2009) An update of the oxidation-inflammation theory of aging: the involvement of the immune system in oxi-inflamma-aging. Curr Pharma Des 15:3003–3026

    Article  Google Scholar 

  12. 12.

    Dhabhar FS and McEwen BS (2001) Bidirectional effects of stress and glucocorticoid hormones on immune function: possible explanations for paradoxical observations. In: Ader R, Felten D, Cohen N (eds) Psychoneuroimmunology, Academic Press, pp 301–337

  13. 13.

    Docherty JR (2002) Age-related changes in adrenergic neuroeffector transmission. Auton Neurosci 96:8–12

    CAS  Article  PubMed  Google Scholar 

  14. 14.

    Elenkov IJ, Chrousos GP (1999) Stress hormones. Th1/Th2 patterns, pro/anti-inflammatory cytokines and susceptibility to disease. Trend Endocrinol Metab 10:359–368

    CAS  Article  Google Scholar 

  15. 15.

    Elenkov IJ, Chrousos GP (2002) Stress hormones, pro-inflammatory and anti-inflammatory cytokines, and autoimmunity. Ann NY Aca Sci 966:290–303

    CAS  Article  Google Scholar 

  16. 16.

    Fabris N (1991) Neuroendocrine-immune interactions: a theoretical approach to aging. Arch Gerontol Geriat 12:219–230

    CAS  Article  Google Scholar 

  17. 17.

    Forner MA, Barriga C, Rodríguez AB, Ortega E (1995) A study of the role of corticosterone as a mediator in exercise-induced stimulation of murine macrophage phagocytosis. J Physiol 488:789–794

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  18. 18.

    García JJ, Martín-Cordero L, Hinchado MD, Bote ME, Ortega E (2013) Effects of habitual exercise on the eHsp72-induced release of inflammatory cytokines by macrophages from obese Zucker rats. Int J Sports Med 34:559–564

    PubMed  Google Scholar 

  19. 19.

    Giraldo E, García JJ, Hinchado MD, Ortega E (2009) 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 16:237–244

    CAS  Article  PubMed  Google Scholar 

  20. 20.

    Giraldo E, Martin-Cordero L, García JJ, Gehrmann M, Multhoff G, Ortega E (2010) Exercise-induced extracellular 72 kDa heat shock protein (Hsp72) stimulates neutrophil phagocytic and fungicidal capacities via TLR-2. Eur J Appl Physiol 108:217–225

    CAS  Article  PubMed  Google Scholar 

  21. 21.

    Giraldo E, Multhoff G, Ortega E (2010) Noradrenaline increases the expression and release of Hsp72 by human neutrophils. Brain Behav Immun 24:672–677

    CAS  Article  PubMed  Google Scholar 

  22. 22.

    Gleeson M, Bishop NC, Stensel DJ, Lindley MR, Mastana SM, Nimmo MA (2011) The anti-inflammatory effects of exercise: mechanisms and implications for the prevention and treatment of disease. Nat Rev Immunol 11:607–615

    CAS  Article  PubMed  Google Scholar 

  23. 23.

    Ji LL (2006) Oxidative stress and antioxidative defense: effects of aging and exercise. In: Alessio HM, Hagerman AE (eds), Oxidative Stress, Exercise, and Aging, Imperial College Press pp 85–108

  24. 24.

    Kohut ML, Senchina DS (2004) Reversing age-associated immunosenescence via exercise. Exerc Immunol Rev 10:6–41

    PubMed  Google Scholar 

  25. 25.

    Martín-Cordero L, García JJ, Hinchado MD, Ortega E (2011) The interleukin-6 and noradrenaline mediated inflammation-stress feedback mechanisms is dysregulated in metabolic syndrome: effect of exercise. Cardiovasc Diabetol 10:42. doi:10.1186/1475-2840-10-42

    Article  PubMed  PubMed Central  Google Scholar 

  26. 26.

    Martín-Cordero L, García JJ, Ortega E (2013) Noradrenaline-mediated inhibition of inflammatory cytokines is altered in macrophages from obese Zucker rats: effect of habitual exercise. Endocr Metab Immune Disord Drug Targets 13:234–239

    Article  PubMed  Google Scholar 

  27. 27.

    Martín-Cordero L, Reis F, García JJ, Teixeira F, Ortega E (2013) Effect of exercise without diet on functional capacity of peritoneal macrophages and TNF-alpha levels in blood and in adipose tissue in the obese Zucker rat model of the metabolic syndrome. Proc Nutr Soc 72:E76

    Article  Google Scholar 

  28. 28.

    Mattson MP (2008) Hormesis defined. Ageing Res Rev 7:1–7

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  29. 29.

    Michishita R, Shono N, Inoue T, Tsuruta T, Node K (2010) Effect of exercise therapy on monocytes and neutrophil counts in overweight women. Am J Med Sci 339:152–156

    Article  PubMed  Google Scholar 

  30. 30.

    Ortega E (2003) Neuroendocrine mediators in the modulation of phagocytosis by exercise: physiological implications. Exerc Immunol Rev 9:70–93

    PubMed  Google Scholar 

  31. 31.

    Ortega Rincón E (1994) Influence of exercise on phagocytosis. Int J Sports Med 15:S172–S178

    Article  PubMed  Google Scholar 

  32. 32.

    Ortega E, Bote ME, Besedovsky HO, del Rey A (2012) Hsp72, inflammation, and aging: causes, consequences, and perspectives. Ann NY Acad Sci 1261:125–131

    Article  Google Scholar 

  33. 33.

    Ortega E, Bote ME, Giraldo E, García JJ (2012) Aquatic exercise improves the monocyte pro- and anti-inflammatory cytokine production balance in fibromyalgia patients. Scand J Med Sci Sports 22:104–112

    CAS  Article  PubMed  Google Scholar 

  34. 34.

    Ortega E, Forner MA, Barriga C (1997) Exercise-induced stimulation of murine macrophage chemotaxis: role of corticosterone and prolactin as mediators. J Physiol 298:729–734

    Article  Google Scholar 

  35. 35.

    Ortega E, García JJ, la Fuente D (2000) Modulation of adherence and chemotaxis of macrophages by norepinephrine. Influence of aging. Mol Cell Biochem 203:113–117

    CAS  Article  PubMed  Google Scholar 

  36. 36.

    Ortega E, García JJ, Sáez MC, la Fuente D (2000) Changes with aging in the modulation of macrophages by norepinephrine. Mech Ageing Dev 118:103–114

    CAS  Article  PubMed  Google Scholar 

  37. 37.

    Ortega E, Hinchado MD, Martín-Cordero L, Asea A (2009) The effect of stress-inducible extracellular Hsp72 on human neutrophil chemotaxis: a role during acute intense exercise. Stress 12:240–249

    CAS  Article  PubMed  Google Scholar 

  38. 38.

    Phillips MD, Flynn MG, McFarlin BK, Stewart LK, Ji H, Liu J, Timmerman KL, Kim JK (2001) Proinflammatory cytokines in response to acute and chronic exercise in women aged 65–89 years (abstract). Med Sci Sports Exer 33:S69

    Google Scholar 

  39. 39.

    Ploeger HE, Takken T, de Greef MH, Timmons BW (2009) The effects of acute and chronic exercise on inflammatory markers in children and adults with a chronic inflammatory disease: a systematic review. Exer Immunol Rev 15:6–41

    Google Scholar 

  40. 40.

    Rattan SI, Demirovic D (2009) Hormesis can and does work in humans. Dose Response 8:58–63

    Article  PubMed  PubMed Central  Google Scholar 

  41. 41.

    Shimazu T, Tamura N, Shimazu Z (2005) Aging of the autonomic nervous system. Nippon Rinsho 63:973–977

    PubMed  Google Scholar 

  42. 42.

    Teixeira-Lemos E, Nunes S, Teixeira F, Reis F (2011) Regular physical exercise training assists in preventing type 2 diabetes development: focus on its antioxidant and anti-inflammatory properties. Cardiovascular Diabetol 10:12. doi:10.1186/1475-2840-10-12

    Article  Google Scholar 

  43. 43.

    Teixeira de Lemos E, Pinto R, Oliveira J, Garrido P, Sereno J, Mascarenhas-Melo F, Páscoa-Pinheiro J, Texeira F, Reis F (2011) Differential effects of acute (extenuating) and chronic (training) exercise on inflammation and oxidative stress status in an animal model of type 2 diabetes mellitus. Mediators Inflamma 2011:253061. doi:10.1155/2011/253061

    Article  Google Scholar 

  44. 44.

    Teixeira de Lemos E, Reis F, Baptista S, Pinto R, Sepodes B, Vala H, Rocha-Pereira P, Correia da Silva G, Teixeira N, Silva AS, Carvalho L, Teixeira F, Das UN (2009) Exercise training decrease proinflammatory profile in Zucker diabetic (type 2) fatty rats. Nutrition 25:330–339

    CAS  Article  PubMed  Google Scholar 

  45. 45.

    Walsh NP, Gleeson M, Shephard RJ, Gleeson M, Woods JA, Bishop NC, Fleshner M, Gree C, Pedersen BK, Hoffman-Goetz L, Rogers CJ, Northoff H, Abbasi A, Simon P (2011) Position statement. Part one: immune function and exercise. Exer Immunol Rev 17:6–63

    Google Scholar 

  46. 46.

    Ziegler MG, Lake CR, Kopin IJ (1976) Plasma noradrenaline increases with age. Nature 261:333–335

    CAS  Article  PubMed  Google Scholar 

Download references


I thank Dr R. A. Chatwin for his critical review of the English and Junta de Extremadura-FEDER (GR15041).

Author information



Corresponding author

Correspondence to Eduardo Ortega.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Ortega, E. The “bioregulatory effect of exercise” on the innate/inflammatory responses. J Physiol Biochem 72, 361–369 (2016).

Download citation


  • Exercise
  • Stress
  • Innate and inflammatory responses
  • Bioregulatory effect
  • Hormesis