Effect of a high and low dose of caffeine on antigen-stimulated activation of human natural killer cells after prolonged cycling


Journal Title (Medline/Pubmed accepted abbreviation): Int J Sport Nutr and Exerc Metab.
Year: 2011
Volume: 21
Number: 2
Page numbers: 155-165
doi (if applicable): N/A

Summary of Background and Research Design

Background: Many athletes consume caffeine for its known ergogenic effects, which have been demonstrated with doses as low as 2 mg/kg body mass (~150 to 200 mg). Natural killer (NK) cells are part of the innate immune system and represent the “first line of defense” against viral infections and tumor immune surveillance. However, these immune responses typically decrease after high-intensity exercise. CD69 is a cell surface receptor that appears to indicate a cell’s capability to recognize and respond to immune challenge. The functional capacity of NK cells can therefore be monitored based on expression of CD69. NK-cell activity is inhibited by adenosine, and because caffeine is an adenosine antagonist, the authors theorized that caffeine may help to maintain NK-cell activation, an important defense against the viral infections that often occur in the recovery period after intense exercise.

Hypothesis/purpose of study: To determine the effect of variable doses of caffeine on NK-cell activation after intense exercise, as assessed by the early-activation marker CD69. An initial pilot study was also conducted to evaluate the effects of caffeine doses on antigen-stimulated NK-cell activation at rest.

Subjects: Six healthy participants (mean age, 25 ± 3 yr; weight, 76 ± 6 kg) participated in the pilot study and 12 endurance-trained male cyclists (mean age, 22 ± 2 yr; body mass, 71 ± 6 kg; peak oxygen consumption [VO2peak], 61 ± 4 mL/kg/min; peak power output, 330 ± 25 W) volunteered to participate in the study.

Experimental design: Randomized, crossover

Treatments and protocol: A pilot study (without exercise) was conducted before preliminary testing to determine whether there was any effect of caffeine at doses of 0, 2, or 6 mg/kg body mass on unstimulated and antigen-stimulated lymphocyte activation (as assessed by the early-activation molecule CD69) for a period of 3.5 hours after caffeine ingestion. For the main exercise study, participants were randomly assigned to 1 of 3 trials separated by at least 1 week. A presupplement blood sample was collected after an overnight fast of 12 hours. Participants then ingested 2 (2CAF) or 6 (6CAF) mg/kg of caffeine with 300 mL plain water, or 6 mg/kg of dextrose powder (PLA). Preexercise venous blood samples were taken after 1 hour and, immediately following, participants began cycling on an electromagnetically braked cycle ergometer for 90 minutes at a work rate equivalent to 70% VO2peak (213 ± 22 W). At 20, 50, and 80 minutes of exercise, 1-minute expired-gas samples were collected to determine VO2 and VCO2. Postexercise blood samples were obtained immediately after cessation of exercise, before postexercise body mass (in shorts only) was recorded. A final venous blood sample (1 hr postexercise) was also obtained. Whole blood was analyzed for hematocrit and differential leukocyte counts. Expression of CD3, CD56, and CD69 receptors was analyzed by flow cytometry.

Summary of research findings:
  • In the pilot study, the number of CD3–CD56+ cells was higher 1 hour and 2.5 hours after caffeine ingestion with 6CAF than with PLA or 2CAF, respectively (P < .05).
  • Regarding the main exercise study:
    • Mean exercise intensity, heart rate, respiratory-exchange ratio, fat and carbohydrate oxidation rates, and energy expenditure did not differ across trials.
    • Plasma volume decreased after exercise for all treatment arms.
    • There was a significant interaction effect for the expression of CD69 on unstimulated CD3–CD56+cells, with both 2CAF and 6CAF demonstrating a significant increase 1 hour postexercise compared with PLA (both P < .05).

Interpretation of findings/Key practice applications:

The study suggests that ingesting caffeine 1 hour before exercise can increase the natural state of activation of circulating NK cells and the expression of CD69 on stimulated NK cells 1 hour after high-intensity prolonged cycling. The authors suggest that these findings reflect either an overriding antagonistic effect of caffeine on adenosine receptors (eg, A2A) and/or a caffeine-influenced epinephrine-mediated mobilization of a specific population of activated NK cells. The practical application of these results suggests that the low dose of caffeine, as well as being ergogenic, may have the potential to strengthen an athlete’s first line of defense against infectious agents after high-intensity exercise. However, it is difficult to extrapolate an enhancement in NK-cell activation to overall improvement in an athlete’s immunity, as this study relates to one particular cellular response and may not accurately represent what is happening to the rest of the immune system. Additionally, this study used whole-blood cultures when stimulating cells, and therefore could not preclude the possibility of the results being indirectly induced by activation of other cell types.
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