Chronic exercise modulates the cellular immunity and its cannabinoid receptors expression

Autoři: Salvador Valencia-Sánchez aff001;  Karen Elizabeth Nava-Castro aff002;  Margarita Isabel Palacios-Arreola aff002;  Oscar Prospéro-García aff003;  Jorge Morales-Montor aff004;  René Drucker-Colín aff001
Působiště autorů: Instituto de Fisiología Celular, Departamento de Neuropatología Molecular, Universidad Nacional Autónoma de México, Circuito Exterior s/n, Ciudad Universitaria, Ciudad de México, México aff001;  Genotoxicología y Mutagénesis Ambientales, Ciencias Ambientales, Centro de Ciencias de la Atmósfera, Ciudad de México, México aff002;  Laboratorio de Cannabinoides, Departamento de Fisiología, Facultad De Medicina, Universidad Nacional Autónoma de México, Circuito Exterior s/n, Ciudad Universitaria, Ciudad de México, México aff003;  Departamento de Inmunología, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, AP, Ciudad de México, México aff004
Vyšlo v časopise: PLoS ONE 14(11)
Kategorie: Research Article
doi: 10.1371/journal.pone.0220542


The impact of performing exercise on the immune system presents contrasting effects on health when performed at different intensities. In addition, the consequences of performing chronic exercise have not been sufficiently studied in contrast to the effects of acute bouts of exercise. The porpoise of this work was to determine the effect that a popular exercise regimen (chronic/moderate/aerobic exercise) has on the proportion of different immune cell subsets, their function and if it affects the cannabinoid system with potentially functional implications on the immune system. A marked increase in several immune cell subsets and their expression of cannabinoid receptors was expected, as well as an enhanced proliferative and cytotoxic activity by total splenocytes in exercised animals. For this study male Wistar rats performed treadmill running 5 times a week for a period of 10 weeks, at moderate intensity. Our results showed a significant decrease in lymphocyte subpopulations (CD4+, Tγδ, and CD45 RA+ cells) and an increase in the cannabinoid receptors expression in those same cell. Although functional assays did not reveal any variation in total immunoglobulin production or NK cells cytotoxic activity, proliferative capability of total splenocytes increased in trained rats. Our results further support the notion that exercise affects the immunological system and extends the description of underlying mechanisms mediating such effects. Altogether, our results contribute to the understanding of the benefits of exercise on the practitioner´s general health.

Klíčová slova:

Analysis of variance – B cells – Exercise – Immune cells – Immune response – Lymphocytes – T cells – Cannabinoids


1. Santos RVT, Caperuto É C, Costa Rosa LFBP. Effects of acute exhaustive physical exercise upon glutamine metabolism of lymphocytes from trained rats. Life Sci. 2007;80(6):573–8. doi: 10.1016/j.lfs.2006.10.015 17123550

2. Freidenreich DJ, Volek JS. Immune responses to resistance exercise. Exerc Immunol Rev. 2012;18:8–41. 22876721

3. Freidenreich DJ, Volek JS. The Immune Response to Exercise [Internet]. Nutrition and Enhanced Sports Performance. Elsevier Inc.; 2013. 95–101 p. Available from:

4. Gleeson M, Bishop NC, Stensel DJ, Lindley MR, Mastana SS, Nimmo MA. The anti-inflammatory effects of exercise: mechanisms and implications for the prevention and treatment of disease. Nat Rev Immunol [Internet]. 2011 Sep 5;11(9):607–15. Available from: doi: 10.1038/nri3041 21818123

5. Ropelle ER, Flores MB, Cintra DE, Rocha GZ, Pauli JR, Morari J, et al. IL-6 and IL-10 anti-inflammatory activity links exercise to hypothalamic insulin and leptin sensitivity through IKKβ and ER stress inhibition. PLoS Biol. 2010;8(8):31–2.

6. Handschin C, Spiegelman BM. The role of exercise and PGC1α in inflammation and chronic disease. 2008;454(7203):463–9. doi: 10.1038/nature07206 18650917

7. GROUP DPPR. Reduction in the Incidence of Type 2 Diabetes with Lifestyle Intervention or Metformin. N Engl J Med [Internet]. 2002 Feb 7;346(6):393–403. Available from: doi: 10.1056/NEJMoa012512 11832527

8. Gustafson MP, DiCostanzo AC, Wheatley CM, Kim CH, Bornschlegl S, Gastineau DA, et al. A systems biology approach to investigating the influence of exercise and fitness on the composition of leukocytes in peripheral blood. J Immunother Cancer. 2017;5(1):1–14.

9. LaVoy EC, Hussain M, Reed J, Kunz H, Pistillo M, Bigley AB, et al. T‐cell redeployment and intracellular cytokine expression following exercise: effects of exercise intensity and cytomegalovirus infection. Physiol Rep [Internet]. 2017;5(1):e13070. Available from: 28087817

10. Pedersen BK, Hoffman-goetz L. Exercise and the Immune System: Regulation, Integration, and Adaptation. Society. 2000;80(3):1055–81.

11. Sugiura H, Sugiura H, Nishida H, Inaba R, Mirbod SM, Iwata H. Effects of different durations of exercise on macrophage functions in mice Effects of different durations of exercise on macrophage functions in mice. J Appl Physiol. 2001;789–94.

12. Campbell JP, Turner JE, Campbell JP, Turner JE. Debunking the Myth of Exercise- Induced Immune Suppression: Redefining the Impact of Exercise on Immunological Health Across the Lifespan. 2018;9(April):1–21.

13. Lancaster G, Halson S, Khan Q, Drysadale P, Wallace F, Jeukendrup AE, et al. Effects of acute exhaustive exercise and chronic exercise training on type 1 and type 2 T lymphocytes. Exerc Immunol Rev [Internet]. 2004;10:91–104. Available from: 15633589

14. Wang J, Song H, Tang X, Yang Y, Vieira VJ, Niu Y, et al. Effect of exercise training intensity on murine T-regulatory cells and vaccination response. Scand J Med Sci Sports [Internet]. 2012 Oct [cited 2012 Oct 10];22(5):643–52. Available from: doi: 10.1111/j.1600-0838.2010.01288.x 21410542

15. Palmer CS, Cherry CL, Sada-Ovalle I, Singh A, Crowe SM. Glucose Metabolism in T Cells and Monocytes: New Perspectives in HIV Pathogenesis. EBioMedicine [Internet]. 2016 Apr;6:31–41. Available from: doi: 10.1016/j.ebiom.2016.02.012 27211546

16. Palmer CS, Ostrowski M, Balderson B, Christian N, Crowe SM. Glucose metabolism regulates T cell activation, differentiation, and functions. Front Immunol. 2015;6(JAN):1–6. doi: 10.3389/fimmu.2015.00001 25657648

17. Padgett D a. Glaser R. How stress influences the immune response. Trends Immunol. 2003;24(8):444–8. doi: 10.1016/s1471-4906(03)00173-x 12909458

18. Sparling PB, Giuffrida a, Piomelli D, Rosskopf L, Dietrich a. Exercise activates the endocannabinoid system. Neuroreport [Internet]. 2003 Dec 2 [cited 2012 Aug 22];14(17):2209–11. Available from: doi: 10.1097/00001756-200312020-00015 14625449

19. Heyman E, Gamelin F, Goekint M, Piscitelli F, Roelands B, Leclair E, et al. Intense exercise increases circulating endocannabinoid and BDNF levels in humans–—Possible implications for reward and depression. Psychoneuroendocrinology. 2012;37:844–51. doi: 10.1016/j.psyneuen.2011.09.017 22029953

20. Galdino G, Romero TRL, Silva JFP, Aguiar DC, De Paula AM, Cruz JS, et al. The endocannabinoid system mediates aerobic exercise-induced antinociception in rats. Neuropharmacology [Internet]. 2014;77:313–24. Available from: doi: 10.1016/j.neuropharm.2013.09.022 24148812

21. Galiègue S, Mary S, Marchand J, Dussossoy D, Carrikre D, Camyon P, et al. Expression of central and peripheral cannabinoid receptors in human immune tissues and leukocyte subpopulations. Eur J Biochem. 1995;61(232):54–61.

22. Klein TW, Newton C, Friedman H. Cannabinoid receptors and immunity. Immunol Today [Internet]. 1998 Aug;19(8):373–81. Available from: doi: 10.1016/s0167-5699(98)01300-0 9709506

23. Tanasescu R, Constantinescu CS. Cannabinoids and the immune system: an overview. Immunobiology [Internet]. 2010 Aug [cited 2012 Jul 23];215(8):588–97. Available from: doi: 10.1016/j.imbio.2009.12.005 20153077

24. Cencioni MT, Chiurchiù V, Catanzaro G, Borsellino G, Bernardi G, Battistini L, et al. Anandamide suppresses proliferation and cytokine release from primary human T-lymphocytes mainly via CB2 receptors. PLoS One. 2010;5(1):2–11.

25. Malek N, Popiolek-Barczyk K, Mika J, Przewlocka B, Starowicz K. Anandamide, acting via CB2 receptors, alleviates LPS-induced neuroinflammation in rat primary microglial cultures. Neural Plast. 2015;2015.

26. Pilis W., Zarzezny R., Langfort J., Kactuba-Uscitko H., Nazar K., Wojtyna J. Anaerobic treshold in rats. Comp Biochem Physiol. 1993;(106):285–9.

27. Carvalho JF, Masuda MO, Pompeu FAMS. Method for diagnosis and control of aerobic training in rats based on lactate threshold. 2005;140:409–13. doi: 10.1016/j.cbpb.2004.12.002 15936699

28. Radom-Aizik S, Zaldivar F, Haddad F, Cooper DM. Impact of brief exercise on peripheral blood NK cell gene and microRNA expression in young adults. J Appl Physiol [Internet]. 2013;114(5):628–36. Available from: doi: 10.1152/japplphysiol.01341.2012 23288554

29. Murphy E a, Davis JM, Brown a S, Carmichael MD, Van Rooijen N, Ghaffar a, et al. Role of lung macrophages on susceptibility to respiratory infection following short-term moderate exercise training. Am J Physiol Regul Integr Comp Physiol [Internet]. 2004;287(6):R1354–8. Available from: doi: 10.1152/ajpregu.00274.2004 15308485

30. Syu G-D, Chen H-I, Jen CJ. Differential effects of acute and chronic exercise on human neutrophil functions. Med Sci Sports Exerc [Internet]. 2012;44(6):1021–7. Available from: doi: 10.1249/MSS.0b013e3182408639 22130467

31. Sugiura H, Sugiura H, Nishida H, Inaba R, Mirbod SM, Iwata H. Effects of different durations of exercise on macrophage functions in mice Effects of different durations of exercise on macrophage functions in mice. J Appl Physiol. 2012;789–94.

32. Saito Y, Kusaka Y, Shimada M. Effects of exercise intensity on circulating leukocyte subpopulations. Environ Health Prev Med [Internet]. 2003;8(1):18–22. Available from: doi: 10.1007/BF02897939 21432111

33. Davis JM, Murphy E a, Brown a S, Carmichael MD, Ghaffar a, Mayer EP. Effects of moderate exercise and oat beta-glucan on innate immune function and susceptibility to respiratory infection. Am J Physiol Regul Integr Comp Physiol. 2004;286(2):R366–72. doi: 10.1152/ajpregu.00304.2003 14551169

34. Slusher AL, Zúñiga TM, Acevedo EO. Maximal Exercise Alters the Inflammatory Phenotype and Response of Mononuclear Cells [Internet]. Medicine & Science in Sports & Exercise. 2017. 1 p. Available from:

35. Matthews CE, Ockene IR a S, Freedson PS, Rosal MC, Merriam P a, Hebert JR. Moderate to vigorous physical activity and risk of upper-repiratory tract infection. Med Sci Sport Exerc. 2002;34(8):1242–8.

36. Parsons LM, Denton D, Egan G, Mckinley M, Shade R, Lancaster J, et al. Neuroimaging evidence implicating cerebellum in support of sensorycognitive processes associated with thirst. 2000;97(5). doi: 10.1073/pnas.040555497 10688891

37. MacKinnon LT. Special feature for the Olympics: effects of exercise on the immune system: overtraining effects on immunity and performance in athletes. Immunol Cell Biol [Internet]. 2000 Oct;78(5):502–9. Available from: doi: 10.1111/j.1440-1711.2000.t01-7-.x 11050533

38. Córdova A, Sureda A, Tur JA, Pons A. Immune response to exercise in elite sportsmen during the competitive season. J Physiol Biochem [Internet]. 2010 Mar 29;66(1):1–6. Available from: doi: 10.1007/s13105-010-0001-2 20428993

39. Lin YS, Jan MS, Chen HI. The effect of chronic and acute exercise on immunity in rats. / Effet de l ‘ exercice chronique et aigu sur l ‘ immunite chez des rats. Int J Sports Med [Internet]. 1993;14(2):86–92. Available from: doi: 10.1055/s-2007-1021151 8463030

40. Blannin a K, Chatwin LJ, Cave R, Gleeson M. Effects of submaximal cycling and long-term endurance training on neutrophil phagocytic activity in middle aged men. Br J Sports Med [Internet]. 1996 Jun 1;30(2):125–9. Available from: doi: 10.1136/bjsm.30.2.125 8799596

41. Chiurchiu V, Battistini L, Maccarrone M. Endocannabinoid signalling in innate and adaptive immunity. Immunology. 2015;144(3):352–64. doi: 10.1111/imm.12441 25585882

42. Greineisen WE, Turner H. Immunoactive effects of cannabinoids: considerations for the therapeutic use of cannabinoid receptor agonists and antagonists. Int Immunopharmacol [Internet]. 2010 May [cited 2013 Mar 7];10(5):547–55. Available from: doi: 10.1016/j.intimp.2010.02.012 20219697

43. Galgglje S, Mary S, Marchand J, Dussossoy D, Carrikre D, Camyon P, et al. Expression of central and peripheral cannabinoid receptors in human immune tissues and leukocyte subpopulations. Signals. 1995;61:54–61.

44. Bouaboula M, Rinaldi M, Carayon P, Carillon C, Delpech B, Shire D, et al. Cannabinoid-receptor expression in human leukocytes. Eur J Biochem [Internet]. 1993;214(1):173–80. Available from: doi: 10.1111/j.1432-1033.1993.tb17910.x 8508790

45. Graham ES, Angel CE, Schwarcz LE, Dunbar PR, Glass M. Detailed characterisation of CB2 receptor protein expression in peripheral blood immune cells from healthy human volunteers using flow cytometry. Int J Immunopathol Pharmacol. 2010;23(1):25–34. doi: 10.1177/039463201002300103 20377992

46. Lee SF, Newton C, Widen R, Friedman H, Klein TW. Differential expression of cannabinoid CB 2 receptor mRNA in mouse immune cell subpopulations and following B cell stimulation. Eur J Pharmacol. 2001;235–41.

47. Noe SN, Newton C, Widen R, Friedman H, Klein TW. Anti-CD40, anti-CD3, and IL-2 stimulation induce contrasting changes in CB1 mRNA expression in mouse splenocytes. 2000;110:161–7. doi: 10.1016/s0165-5728(00)00349-0 11024546

48. Amancio-Belmont O, Becerril Meléndez AL, Ruiz-Contreras AE, Méndez-Díaz M, Prospéro-García O. Opposed cannabinoid 1 receptor (CB1R) expression in the prefrontal cortex vs. nucleus accumbens is associated with alcohol consumption in male rats. Brain Res [Internet]. 2019;1725(September):146485. Available from: doi: 10.1016/j.brainres.2019.146485 31568767

49. Piszcz J a, Lemancewicz D, Kloczko J, Dzieciol J, Rusak M, Dabrowska M. Cannabinoid receptors expression in bone marrow trephine biopsy of chronic lymphocytic leukaemia patients treated with purine analogues. Exp Oncol [Internet]. 2007 Sep;29(3):221–5. Available from: 18004250

Článek vyšel v časopise


2019 Číslo 11