Thomas Rohde

Pro- and anti-inflammatory cytokine balance in strenuous exercise in humans

1 The present study investigates to what extent and by which time course prolonged strenuous exercise influences the plasma concentration of pro‐inflammatory and inflammation responsive cytokines as well as cytokine inhibitors and anti‐inflammatory cytokines. 2 Ten male subjects (median age 27.5 years, range 24–37) completed the Copenhagen Marathon 1997 (median running time 3:26 (h:min), range 2:40–4:20). Blood samples were obtained before, immediately after and then every 30 min in a 4 h post‐exercise recovery period. 3 The plasma concentrations of tumour necrosis factor (TNF)α, interleukin (IL)‐1β, IL‐6, IL‐1ra, sTNF‐r1, sTNF‐r2 and IL‐10 were measured by enzyme‐linked immunosorbent assay (ELISA). The highest concentration of IL‐6 was found immediately after the race, whereas IL‐1ra peaked 1 h post exercise (128‐fold and 39‐fold increase, respectively, as compared with the pre‐exercise values). The plasma level of IL‐1β, TNFα, sTNF‐r1 and sTNF‐r2 peaked in the first hour after the exercise (2.1‐, 2.3‐, 2.7‐ and 1.6‐fold, respectively). The plasma level of IL‐10 showed a 27‐fold increase immediately post exercise. 4 In conclusion, strenuous exercise induces an increase in the pro‐inflammatory cytokines TNFα and IL‐1β and a dramatic increase in the inflammation responsive cytokine IL‐6. This is balanced by the release of cytokine inhibitors (IL‐1ra, sTNF‐r1 and sTNF‐r2) and the anti‐inflammatory cytokine IL‐10. The study suggests that cytokine inhibitors and anti‐inflammatory cytokines restrict the magnitude and duration of the inflammatory response to exercise.

Evidence that interleukin‐6 is produced in human skeletal muscle during prolonged running

1 This study was performed to test the hypothesis that inflammatory cytokines are produced in skeletal muscle in response to prolonged intense exercise. Muscle biopsies and blood samples were collected from runners before, immediately after, and 2 h after a marathon race. 2 The concentration of interleukin (IL)‐6 protein in plasma increased from 1.5 ± 0.7 to 94.4 ± 12.6 pg ml−1 immediately post‐exercise and to 22.1 ± 3.8 pg ml−1 2 h post‐exercise. IL‐1 receptor antagonist (IL‐1ra) protein in plasma increased from 123 ± 23 to 2795 ± 551 pg ml−1, and increased further to 4119 ± 527 pg ml−1 2 h post‐exercise. 3 The comparative polymerase chain reaction technique was used to evaluate mRNA for IL‐6, IL‐1ra, IL‐1β and tumour necrosis factor (TNF)‐α in skeletal muscle and blood mononuclear cells (BMNC) (n= 8). Before exercise, mRNA for IL‐6 could not be detected either in muscle or in BMNC, and was only detectable in muscle biopsies (5 out of 8) after exercise. Increased amounts of mRNA for IL‐1ra were found in two muscle biopsies and five BMNC samples, and increased amounts of IL‐1β mRNA were found in one muscle and four BMNC samples after exercise. TNF‐α mRNA was not detected in any samples. 4 This study suggests that exercise‐induced destruction of muscle fibres in skeletal muscles may trigger local production of IL‐6, which stimulates the production of IL‐1ra from circulating BMNC.

The cytokine response to strenuous exercise

Strenuous exercise is accompanied by an increase in circulating proinflammatory and inflammation responsive cytokines, having some similarities with the response to sepsis and trauma. The sequential release of tumour necrosis factor-alpha, interleukin (IL) 1 beta, IL-6, and IL-1 receptor antagonist (IL-1ra) in the blood is comparable to that observed in relation to bacterial diseases. Eccentric exercise is associated with an increase in serum IL-6 concentrations and is significantly correlated with the concentration of creatine kinase (CK) in the following days, whereas no changes are found after the concentric exercise; this demonstrates a close association between exercise-induced muscle damage and increased serum levels of IL-6. The time course of cytokine production, the close association with muscle damage, and the finding of mRNA-IL-6 in skeletal muscle biopsies after intense exercise all support the idea that during eccentric exercise myofibers are mechanically damaged and that this process stimulates the local production of inflammatory cytokines. It remains to be shown whether systemic endotoxemia during exercise is also a cause of elevated levels of cytokines in the plasma. The present review also discusses the possible roles of protein breakdown, delayed onset muscle soreness, and clinical implications of the acute-phase response following exercise.

Chemokines are elevated in plasma after strenuous exercise in humans

Abstract During the last few years much attention has been paid to the chemokines. Chemokine receptors are necessary to render a target permissive for infection by the human immunodeficiency virus (HIV) and high concentrations of chemokines have been shown to protect against the progression of HIV disease towards death. In the present study, we investigated the capability of strenuous exercise to induce elevated plasma concentrations of the chemokines interleukin (IL)-8, macrophage inflammatory protein (MIP)-1α and MIP-1β. Eight male athletes completed the Copenhagen Marathon 1997. Blood was sampled before, immediately after the run and every 30 min during a 4 h recovery period. Plasma chemokine concentrations were measured using enzyme-linked immunosorbent assays. The IL-8, MIP-1α and MIP-1β concentrations all peaked 0.5 h after the run when they were 6.7-fold, 3.5-fold and 4.1-fold increased, respectively. The elevated concentrations of chemokines in plasma after exercise could have implications for HIV-infected individuals; a possibility that needs further investigation.

Effect of glutamine supplementation on changes in the immune system induced by repeated exercise

UNLABELLED The ability of lymphocytes to proliferate and generate lymphokine activated killer (LAK) cell activity in vitro is dependent on glutamine. In relation to intense exercise the lymphocyte concentration, the proliferative response, the natural killer and LAK cell activity, and the plasma glutamine concentration decline. It has been hypothesized that in relation to physical activity a lack of glutamine may temporarily affect the function of the immune system. PURPOSE The purpose of this study was to examine the influence of glutamine supplementation on exercise-induced immune changes. METHODS In a randomized cross-over placebo-controlled study, eight healthy male subjects performed three bouts of ergometer bicycle exercise lasting 60, 45, and 30 min at 75% of their VO2max separated by 2 h of rest. RESULTS The arterial plasma glutamine concentration declined from 508 +/- 35 (pre-exercise) to 402 +/- 38 microM (2 h after the last exercise bout) in the placebo trial and was maintained above pre-exercise levels in the glutamine supplementation trial. The numbers of circulating lymphocytes and the phytohemagglutinin-stimulated lymphocyte proliferative response declined 2 h after, respectively, during each bout of exercise, whereas the LAK cell activity declined 2 h after the third bout. Glutamine supplementation in vivo, given in the described doses at the specific times, did not influence these changes. CONCLUSION The present study does not appear to support the hypothesis that those aspects of postexercise immune changes studied are caused by decreased plasma glutamine concentrations.

The immune system and serum glutamine during a triathlon

This study examined the influence of a triathlon on the immune system and on serum amino acid concentrations. Eight male triathletes swam 2500 m, bicycled 81 km, and ran 19 km. The concentration of total serum amino acids decreased during the race, with the lowest values occurring 2 h postexercise. Similarly, serum glutamine concentration declined from 468 (SEM 24) (prerace) to 318 (SEM 20) μmoll−1 (2 h postrace) and the natural killer (NK) and lymphokine activated killer (LAK) cell activities were suppressed 2 h postexercise (P < 0.05). Blood mononuclear cell proliferation decreased during exercise with the lowest value observed after running. The leucocyte concentration increased during and after exercise due to an increase in the concentration of neutrophils and monocytes. There was no significant change in lymphocyte concentration during or after the exercise. The plasma concentration of interleukin-6 did not change and the plasma concentration of interleukin-1β and tumor necrosis factor-α were below detection limits. The LAK cell cytotoxicity, but not NK cell activity or proliferative response, was significantly correlated with serum glutamine concentrations (r = 0.39,P < 0.01). This study confirms that prolonged endurance exercise results in changes in the cytotoxic function of the NK and LAK cells as well as the proliferative response. The time-course of changes in serum glutamine concentrations were best parallelled by changes in LAK cell activities.

Glutamine, Lymphocyte Proliferation and Cytokine Production

The present in vitro study was conducted to examine how glutamine influences the lymphocyte function. Glutamine had no effect on the production of interleukin‐1β, interleukin‐6 or tumour necrosis factor‐α, but influenced the production of interleukin‐2 and interferon‐γ. Glutamate, leucine, isoleucine and valine (substrates for glutamine production), or the combination of glutamate and leucine, did not influence the lymphocyte proliferative response or the cytokine production. In conclusion, glutamine influenced the production of some T‐cell‐derived cytokines, and is thereby important for optimal lymphocyte proliferation. Furthermore, the results show that lymphocytes are not capable of producing glutamine.

Competitive sustained exercise in humans, lymphokine activated killer cell activity, and glutamine – an intervention study

This study examined whether oral glutamine supplementation abolishes some of the exercise-induced changes in lymphocyte functions following long-term intense exercise. A group of 16 marathon runners participating in The Copenhagen Marathon 1996 were placed randomly in either a placebo (n = 7) or a glutamine receiving group (n = 9). Each subject received four doses of either placebo or glutamine (100 mg · kg−1) administered at 0, 30, 60, and 90-min post-race. In the placebo group the plasma glutamine concentrations were lower than pre-race values during the post-exercise period [mean 647 (SEM 32) compared to 470 (SEM 22) μmol · l−1 90-min post-race, P < 0.05] whereas glutamine supplementation maintained the plasma glutamine concentration (at ∼750 μmol · l−1). Glutamine supplementation in vivo had no effect on the lymphokine activated killer (LAK) cell activity, the proliferative responses or the exercise-induced changes in concentrations or percentages of any of the leucocyte subpopulations examined. Glutamine addition in in vitro studies enhanced the proliferative response in both groups. These data would suggest that decreased plasma glutamine concentrations post-exercise are not responsible for exercise-induced decrease in LAK activity and that the influence of glutamine in vitro is not dependent on the plasma glutamine concentration at the time of sampling.

Training and natural immunity: effects of diets rich in fat or carbohydrate.

Abstract The purpose of the study was to investigate whether a carbohydrate-rich versus fat-rich diet influenced the effect of training on the immune system. Ten untrained young men ingested a carbohydrate-rich diet [65 energy percent (E%) carbohydrate] and ten subjects a fat-rich diet (62E% fat) while endurance training was performed 3–4 times a week for 7 weeks. Maximal oxygen uptake increased by 11% in both groups. Blood samples for immune monitoring were collected before and at the end of the study. Blood samples were also collected, in parallel, from 20 age-matched subjects, and data from these subjects were used to eliminate day-to-day variation in the immunological tests. Independently of diet, training increased the percentage of CD3–CD16+ CD56+ natural killer (NK) cells from [mean (SEM)] 14(1)% to 20 (3)% (P=0.05), whereas the NK-cell activity, either unstimulated or stimulated with interleukin (IL)-2 or interferon (IFN)-α, did not change. Furthermore, training did not influence the percentages of CD3+, CD4+, CD8+, CD19+ or CD14+ cells. However, when the two diet groups were compared, it was found that the NK-cell activity had increased in the group on the carbohydrate-rich diet [from 16 (3)% to 27 (2)%] and decreased in the group on the fat-rich diet [from 26 (2)% to 20 (4)%] in response to training. The effect of training on unstimulated NK-cell activity was significantly different between the groups (P=0.007). These data indicate that diet manipulation during training may influence natural immunity, and suggest that ingestion of a fat-rich diet during training is detrimental to the immune system compared to the effect of a carbohydrate-rich diet.

Nutrition, exercise and the immune system

Today epidemiological evidence exists which supports the anecdotal impression (Nieman & Henson, 1994) that regular exercise increases resistance to infections such as the common cold (Nash, 1987; Fitzgerald, 1988), whereas hard training is associated with increased respiratory infections (Fitzgerald, 1988). It has become clear that the function of the immune system is enhanced by moderate physical activity and may be somewhat responsible for exercise-related reduction in illness. In contrast, it has been repeatedly shown that intense exercise causes inhibition of the function of the immune system in the recovery phase following intense exercise (Hoffman-Goetz & Pedersen, 1994). Today, much research in exercise immunology is stimulated by the acceptance of exercise as a tool to study the immune system. Exercise can be employed as a model for temporary immunosuppression, which occurs after severe physical stress. Furthermore, exercise associated with muscle damage represents a model of the acute-phase response to local injury. Given the fact that nutrition is a critical determinant of immunocompetence, the potential protective role of nutritional agents in exercise-induced immunosuppression will be discussed.