Caffeine Modifies the Immune and Anti-inflammatory Responses to Short Incremental Cycling Exercise Until Exhaustion in Humans: A Pilot Study

Abstract

Exercise has well-documented effects on immune function with both positive and negative sequelae dependent on intensity, volume, and duration. The immunosuppressive effects of exercise are mediated, in part, by the complex interaction of cytokines, catecholamines, and nutrition. Caffeine has been reported to modulate immune function; however, the interaction with brief exhaustive exercise is not well characterized. It was hypothesized that caffeine would upregulate the cytokine response to intense exercise. Seven male students volunteered to participate in a randomized, double-blinded crossover study where they ingested either caffeine (6 mg/kg) or a maltodextrin placebo (6 mg/kg) 1 h prior to a cycling exercise. The exercise protocol started at 100 W and the intensity was increased by 50 W every two minutes until exhaustion. Serum samples were collected pre-, post-, and 1-h post-exercise and analyzed for IL-4, IL-10, and TGF-β1. Caffeine ingestion increased time to exhaustion (P=0.005; Effect Size [ES]=1.33), IL-4 (P=0.004; ES=2.34), IL-10 (P=0.047; ES=0.41±0.57), and TGF-β1 (P=0.013; ES=0.76). The accentuated response of the cytokines may have important ramifications due to their potent anti-inflammatory and immunoregulatory properties. Specifically, the 6 mg/kg caffeine dose not only improved exercise performance but the cytokine data is indicative of an upregulated inflammatory response and an enhancement of the anti-inflammatory benefits of exercise.

Keywords

Th-2 cells / Exercise / Anti-inflammatory / Active immune responses / 1,3,7 trimethylxanthine

References

[1] Arauz J, Zarco N, Segovia J, Shibayama M, Tsutsumi V, Muriel P. Caffeine prevents experimental liver fibrosis by blocking the expression of TGF-beta. Eur J Gastroenterol Hepatol.. 2014, 26(2): 164-173

[2] Beaven CM, Hopkins WG, Hansen KT, Wood MR, Cronin JB, Lowe TE. Dose effect of caffeine on testosterone and cortisol responses to resistance exercise. Int J Sport Nutr Exerc Metab.. 2008, 18(2): 131-141

[3] Bell DG, Jacobs I, Ellerington K. Effect of caffeine and ephedrine ingestion on anaerobic exercise performance. Med Sci Sports Exerc.. 2001, 33(8): 1399-1403

[4] Bishop NC, Fitzgerald C, Porter PJ, Scanlon GA, Smith AC. Effect of caffeine ingestion on lymphocyte counts and subset activation in vivo following strenuous cycling. Eur J Appl Physiol.. 2005, 93(5–6): 606-613

[5] Couper KN, Blount DG, Riley EM. IL-10: the master regulator of immunity to infection. J Immunol.. 2008, 180(9): 5771-5777

[6] Coutinho AE, Chapman KE. The anti-inflammatory and immunosuppressive effects of glucocorticoids, recent developments and mechanistic insights. Mol Cell Endocrinol.. 2011, 335(1): 2-13

[7] Cullen T, Thomas AW, Webb R, Phillips T, Hughes MG. sIL-6R is related to weekly training mileage and psychological well-being in athletes. Med Sci Sports Exerc.. 2017, 49(6): 1176-1183

[8] Doherty M, Smith PM, Hughes MG, Davison RCR. Caffeine lowers perceptual response and increases power output during high-intensity cycling. J Sports Sci.. 2004, 22(7): 637-643

[9] Dulson DK, Bishop NC. Effect of a high and low dose of caffeine on human lymphocyte activation in response to antigen stimulation. Appl Physiol Nutr Metab.. 2016, 41(2): 224-227

[10] Fletcher DK, Bishop NC. Effect of a high and low dose of caffeine on antigen-stimulated activation of human natural killer cells after prolonged cycling. Int J Sport Nutr Exerc Metab.. 2011, 21(2): 155-165

[11] Freidenreich DJ, Volek JS. Immune responses to resistance exercise. Exerc Immunol Rev. 2012, 18: 8-41

[12] Glaister M, Pattison JR, Muniz-Pumares D, Patterson SD, Foley P. Effects of dietary nitrate, caffeine, and their combination on 20-km cycling time trial performance. J Str Cond Res.. 2015, 29(1): 165-174

[13] Greer F, McLean C, Graham TE. Caffeine, performance, and metabolism during repeated Wingate exercise tests. J Appl Physiol.. 1998, 85(4): 1502-1508

[14] Gressner OA, Lahme B, Rehbein K, Siluschek M, Weiskirchen R, Gressner AM. Pharmacological application of caffeine inhibits TGF-beta-stimulated connective tissue growth factor expression in hepatocytes via PPARgamma and SMAD2/3-dependent pathways. J Hepatol.. 2008, 49(5): 758-767

[15] Hopkins WG, Marshall SW, Batterham AM, Hanin J. Progressive statistics for studies in sports medicine and exercise science. Med Sci Sports Exerc.. 2009, 41(1): 3-13

[16] Horrigan LA, Kelly JP, Connor TJ. Immunomodulatory effects of caffeine: friend or foe?. Pharmacol Ther.. 2006, 111(3): 877-892

[17] Karayigit R, Forbes SC, Osmanov Z, Yilmaz C, Yasli BC, Naderi A, Buyukcelebi H, Benesova D, Gabrys T, Esen O. Low and moderate doses of caffeinated coffee improve repeated sprint performance in female team sport athletes. Biology.. 2022, 11(10): 1498

[18] Levings MK, Bacchetta R, Schulz U, Roncarolo MG. The role of IL-10 and TGF-beta in the differentiation and effector function of T regulatory cells. Int Arch Allergy Immunol.. 2002, 129(4): 263-276

[19] Li MO, Flavell RA. Contextual regulation of inflammation: a duet by transforming growth factor-beta and interleukin-10. Immunity.. 2008, 28(4): 468-476

[20] Natale VM, Brenner IK, Moldoveanu AI, Vasiliou P, Shek P, Shephard RJ. Effects of three different types of exercise on blood leukocyte count during and following exercise. Sao Paulo Med J.. 2003, 121(1): 9-14

[21] Nemet D, Mills PJ, Cooper DM. Effect of intense wrestling exercise on leucocytes and adhesion molecules in adolescent boys. Br J Sports Med.. 2004, 38(2): 154-158

[22] Nieman DC, Nehlsen-Cannarella SL, Markoff PA, Balk-Lamberton AJ, Yang H, Chritton DB, Lee JW, Arabatzis K. The effects of moderate exercise training on natural killer cells and acute upper respiratory tract infections. Int J Sports Med.. 1990, 11(6): 467-473

[23] Nieman DC, Henson DA, Sampson CS, Herring JL, Suttles J, Conley M, Stone MH, Butterworth DE, Davis JM. The acute immune response to exhaustive resistance exercise. Int J Sports Med.. 1995, 16(5): 322-328

[24] Nieman DC, Henson DA, McAnulty SR, McAnulty LS, Morrow JD, Ahmed A, Geward CB. Vitamin E and immunity after the Kona triathlon world championship. Med Sci Sports Exerc.. 2004, 36(8): 1328-1335

[25] Nieman DC, Henson DA, Dumke CL, Lind RH, Shooter LR, Gross SJ. Relationship between salivary IgA secretion and upper respiratory tract infection following a 160-km race. J Sports Med Phys Fitness.. 2006, 46(1): 158-162

[26] Nieman DC, Johanssen LM, Lee JW, Arabatzis K. Infectious episodes in runners before and after the Los Angeles Marathon. J Sports Med Phys Fitness. 1990, 30: 316-328

[27] Northoff H, Berg A, Weinstock C. Similarities and differences of the immune response to exercise and trauma: the IFN-gamma concept. Can J Physiol Pharmacol.. 1998, 76(5): 497-504

[28] Rosenthal LA, Taub DD, Moors MA, Blank KJ. Methylxanthine-induced inhibition of the antigen- and superantigen-specific activation of T and B lymphocytes. Immunopharmacology.. 1992, 24(3): 203-217

[29] Sand KL, Flatebo T, Andersen MB, Maghazachi AA. Effects of exercise on leukocytosis and blood hemostasis in 800 healthy young females and males. World J Exp Med.. 2013, 3(1): 11-20

[30] Sanjabi S, Zenewicz LA, Kamanaka M, Flavell RA. Anti-inflammatory and pro-inflammatory roles of TGF-beta, IL-10, and IL-22 in immunity and autoimmunity. Curr Opin Pharmacol. 2009, 9: 447-453

[31] Seiler KS, Kjerland GØ. Quantifying training intensity distribution in elite endurance athletes: is there evidence for an “optimal” distribution?. Scand J Med Sci Sports.. 2006, 16(1): 49-56

[32] Slavish DC, Graham-Engeland JE, Smyth JM, Engeland CG. Salivary markers of inflammation in response to acute stress. Brain Behav Immun. 2015, 44: 253-269

[33] Spriet LL, Howlett RA. Maughan RJ. Nutrition in sport. 2000, Massachusetts, Blackwell Science Ltd: 379392

[34] Stadheim H, Stensrud T, Brage S, Jensen J. Caffeine increases exercise performance, maximal oxygen uptake and oxygen deficit in elite male endurance athletes. Med Sci Sports Exerc.. 2021, 53(11): 2264-2273

[35] Stöggl T, Sperlich B. Polarized training has greater impact on key endurance variables than threshold, high intensity, or high volume training. Front Physiol. 2014, 5: 33

[36] Stoner L, Lucero AA, Palmer BR, Jones LM, Young JM, Faulkner J. Inflammatory biomarkers for predicting cardiovascular disease. Clin Biochem.. 2013, 46(15): 1353-1371

[37] Tatler AL, Barnes J, Habgood A, Goodwin A, McAnulty RJ, Jenkins G. Caffeine inhibits TGFβ activation in epithelial cells, interrupts fibroblast responses to TGFβ, and reduces established fibrosis in ex vivo precision-cut lung slices. Thorax.. 2017, 71(6): 565-567

[38] Tauler P, Martínez S, Moreno C, Monjo M, Martínez P, Aguiló A. Effects of caffeine on the inflammatory response induced by a 15-km run competition. Med Sci Sports Exerc.. 2013, 45(7): 1269-1276

[39] Tauler P, Martinez S, Martinez P, Lozano L, Moreno C, Aguiló A. Effects of caffeine supplementation on plasma and blood mononuclear cell interleukin-10 levels after exercise. Int J Sport Nutr Exerc Metab.. 2016, 26(1): 8-16

[40] 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. Position statement. Part one: immune function and exercise. Exerc Immunol Rev. 2011, 17: 6-63

Funding

University of Waikato