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. 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. 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. 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.

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. 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. 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. 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.

Acute muscular exercise induces an increased neutrophil count concomitant with recruitment of natural killer (NK), B and T cells to the blood as reflected by an elevation in the total lymphocyte count. Meanwhile, following intense exercise of long duration the lymphocyte count declines, non-MHC-restricted cytotoxicity is suppressed, but the neutrophil concentration increases. In relation to eccentric exercise involving muscle damage, the plasma concentrations of interleukin-1, interleukin-6 and the tumor necrosis factor are elevated. In this review we will propose a model based on the possible roles that stress hormones play a mediating the exercise- related immunological changes: adrenaline and to a lesser degree noradrenaline are responsible for the immediate effects of exercise on lymphocyte subpopulations and cytotoxic activities. The increase in catecholamines and growth hormone mediate the acute effects of exercise on neutrophils, whereas cortisol may be responsible for maintaining lymphopenia and neutrocytosis after exercise of long duration. Lastly, the role of beta-endorphin is less clear, but the cytokine response is closely related to muscle damage and stress hormones do not seem to be directly involved in the elevated cytokine level. Other possible mechanisms of exercise-induced immunomodulation may include the so-called glutamine hypothesis, which is based on the fact that skeletal muscle is an important source of glutamine production and that lymphocytes are dependent on glutamine for optimal growth. Furthermore, physiological changes during exercise, e.g. increased body temperature and decreased oxygen saturation may also in theory contribute to the exercise-induced immunological changes.

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.

In the recovery phase after intense exercise is found suppressed blood concentration of lymphocytes, suppressed natural immunity of blood lymphocytes, decreased concentration of secretory IgA in mucosa, but increased blood concentration of neutrophils and increased levels in the blood of inflammatory cytokines. Thus, after intense long-term exercise, the immune system is characterized by concomitant inflammation and temporary suppression of the cellular immune system, the most pronounced findings being 2-4 h after the exercise. The underlying mechanisms are multifactorial and include neuroendocrinological and metabolic factors. High levels of cytokines, especially interleukin-6, are found in the recovery period after eccentric exercise, and it has been demonstrated that a close association exists between muscle damage and increased levels of interleukin-6.