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Special Communications: Letters to the Editor-in-Chief

When are Antioxidants Effective in Blunting the Cytokine Response to Exercise?: RESPONSE

Nieman, David C.; McAnulty, Steve R.

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Medicine & Science in Sports & Exercise: February 2005 - Volume 37 - Issue 2 - p 344
doi: 10.1249/01.MSS.0000149911.39375.6A
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These comments are insightful and we appreciate the interest in our research. In two randomized double blind studies with vitamin C supplements (4,5) and one study with vitamin E (6), my research team failed to show that antioxidant supplementation attenuates oxidative stress or the large increase in cytokines (specifically, IL-6, IL-10, IL-1ra, and IL-8) that occur during long-distance running (2.5–12 h) or triathlon competition (∼12 h).

When we entered into this series of studies, we hypothesized that vitamins C or E would serve as a useful countermeasures to inflammatory cytokine increases during heavy exertion in support of the growing literature supporting a link between reactive oxygen species (ROS) and cytokines (in particular, IL-10). IL-10 has emerged as an antiinflammatory cytokine with antioxidant properties, and has been hypothesized to play a role in gene expression and the biosynthesis of oxidative stress-related cofactors, such as ROS and inflammatory cytokines (2). But within the context of intense and prolonged exercise, we and others have failed to demonstrate that oxidative stress and increases in cytokines are linked to a significant degree (3,5,6). Thus, we feel that increases in inflammatory cytokines during long-distance running are caused by other more influential factors than oxidative stress, and that attempting to quench ROS with vitamins C or E will meet with failure under most athletic exercise conditions.

You suggest in your letter that the type of exercise (concentric compared to mixed concentric and eccentric exercise) and training status may determine whether antioxidant supplementation is effective in reducing the exercise-induced increase in plasma cytokine levels. We feel that the literature base is too small and conflicting to support your viewpoints. The antioxidant dose, duration of supplementation, and exercise mode and workload vary widely between studies. We doubt that training status is an important confounder of the relationship between antioxidant supplementation and exercise-induced increases in ROS and cytokines. In all the studies you listed and compared to make this point, all of the “trained” subjects were engaging in long endurance running events while the “untrained” subjects were exercising for much shorter times periods. If trained and untrained subjects exercised at the same intensity for the same time period, we doubt that cytokine levels in these groups would respond differently to antioxidant supplementation.

In our vitamin C and E supplementation studies, athletes have exercised for long time periods (2.5–12 h). Perhaps exercise of this magnitude is so stressful to the human body that ROS and cytokine production overwhelms any potential influence of antioxidant supplementation.

Vitamin C and E may work better together than alone. We are intrigued by the study of Fisher et al. (1) in which a mixed supplement of vitamin C and E for 28 d decreased oxidative stress, net release of IL-6 from the leg, and plasma levels of IL-6 and IL-1ra during 3 h of two-legged knee-extensor exercise at 50% maximal power output. However, in this same lab, a vitamin C and E supplement failed to attenuated increases in plasma IL-6 and IL-1ra following 90 min of 5% downhill treadmill running at 75% OV0312O2max (7). What accounts for such discrepancies across studies even within the same lab? We do not know, but at this point we feel that antioxidant supplements do not have a high potential for serving as useful countermeasures to exercise-induced increases in cytokines in endurance athletes.

David C. Nieman

Steve R. McAnulty

Human Performance Laboratory, Department of Health and Exercise Science, Appalachian State University, Boone, NC


1. Fischer, C. P., N. J. Hiscock, M. Penkowa, et al. Supplementation with vitamins C and E inhibits the release of interleukin-6 from contracting human skeletal muscle. J. Physiol. 558(Pt 2):633–645, 2004.
2. Haddad, J. J., and C. S. Fahlman. Redox- and oxidant-mediated regulation of interleukin-10: an anti-inflammatory, antioxidant cytokine? Biochem. Biophys. Res. Commun. 297:163–176, 2002.
3. Mastaloudis, A., J. D. Morrow, D. W. Hopkins, S. Devaraj, and M. G. Traver. Antioxidant supplementation prevents exercise-induced lipid peroxidation, but not inflammation, in ultramarathon runners. Free Radic. Biol. Med. 36:1329–1341, 2004.
4. Nieman, D. C., D. A. Henson, D. E. Butterworth, et al. Vitamin C supplementation does not alter the immune response to 2.5 hours of running. Int. J. Sports Nutr. 7:173–184, 1997.
5. Nieman, D. C., D. A. Henson, S. R. McAnulty, et al. Influence of vitamin C supplementation on oxidative and immune changes following an ultramarathon. J. Appl. Physiol. 92:1970–1977, 2002.
6. Nieman, D. C., D. A. Henson, S. R. McAnulty, et al. Vitamin E and immunity after the Kona triathlon world championship. Med. Sci. Sports Exerc. 36:1328–1335, 2004.
7. Petersen, E. W., K. Ostrowski, T. Ibfelt, et al. Effect of vitamin supplementation on cytokine response and on muscle damage after strenuous exercise. Am. J. Physiol. Cell Physiol. 280:C1570–C1575, 2002.
©2005The American College of Sports Medicine