Kenneth Ostrowski

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.

A trauma‐like elevation of plasma cytokines in humans in response to treadmill running

1 Elevated levels of cytokines, especially interleukin (IL)‐6 and IL‐1ra, can be measured in the plasma of athletes after exhaustive long term exercise. 2 The present study investigates the kinetics of several cytokines and chemokines in ten male athletes before, during and after 2.5 h of treadmill running at 75% of maximal oxygen consumption (VO2,max). Blood was sampled before, every half‐hour during running and every hour in the following 6 h recovery period. 3 The plasma concentration of IL‐6 increased after 30 min of running, and peaked at the end of running with a 25‐fold increase compared with the pre‐exercise value. IL‐1ra increased only after running, and peaked after 2 h of rest with an 18‐fold increase compared with the pre‐exercise value. No changes were found in the concentrations of IL‐1β, tumour necrosis factor (TNF)α, IL‐15 and macrophage inflammatory protein (MIP)‐1β, and the concentrations of IL‐8 and MIP‐1α were below detection limits. 4 The results suggest that very early events in exercise trigger the release of IL‐6, and that the cytokine response to exercise has similarities to that observed after trauma.

Physical activity and plasma interleukin-6 in humans – effect of intensity of exercise

Abstract The present study included data from three marathon races to investigate the hypothesis that a relationship exists between running intensity and elevated concentrations of interleukin (IL)-6 in plasma. The study included a total of 53 subjects whose mean age was 30.6 [95% confidence interval (CI) 1.4] years, mean body mass 77.7 (95%CI 2.0) kg, mean maximal oxygen uptake (V˙O2max) 59.3 (95%CI 1.4) ml · min−1 · kg−1, and who had participated in the Copenhagen Marathons of 1996, 1997 or 1998, achieving a mean running time of 206 (95%CI 7) min. Running intensity was calculated as running speed divided by V˙O2max. The concentration of IL-6 in plasma peaked immediately after the run. There was a negative correlation between peak IL-6 concentration and running time (r=−0.30, P < 0.05) and a positive correlation between peak IL-6 concentration and running intensity (r=0.32, P < 0.05). The IL-1 receptor antagonist (IL-1ra) plasma concentration peaked 1.5 h after the run and there was a positive correlation between the peak plasma concentrations of IL-6 and IL-1ra (r=0.39, P < 0.01). Creatine kinase (CK) plasma concentration peaked on the 1st day after the run, but no association was found between peak concentrations of IL-6 and CK. In conclusion, the results confirmed the hypothesized association between plasma IL-6 concentration and running intensity, but did not confirm the previous finding of a connection between IL-6 plasma concentration and muscle damage.

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.

Muscle contractions induce interleukin-6 mRNA production in rat skeletal muscles

1 The present study explored the hypothesis that interleukin‐6 (IL‐6) might be locally produced in response to skeletal muscle contractions and whether the production might reflect the type of muscle contraction performed. Rats were anaesthetized and the calf muscles of one limb were stimulated electrically for concentric or eccentric contractions (4 × 10 contractions with 1 min of rest between the 4 series, 100 Hz). The contralateral muscles served as unstimulated controls. The mRNA levels for IL‐6, the glucose transport protein GLUT‐4 and β‐actin in the rat muscles (white and red gastrocnemius and soleus) were quantified by quantitative competitive RT‐PCR. 2 The IL‐6 mRNA level, measured 30 min after the stimulation, increased after both eccentric and concentric contractions and there were no significant differences in IL‐6 mRNA levels between the different muscle fibre types. No significant increase in IL‐6 mRNA level was seen in the unstimulated contralateral muscle fibres. 3 No increase in GLUT‐4 mRNA level was detected, indicating that the increase in IL‐6 mRNA level was not due to general changes in transcription. 4 We conclude that IL‐6 is locally produced after muscle contraction, with no significant differences between different muscle fibre types. This local production of IL‐6 is not due to general changes in transcription, since no changes in the level of GLUT‐4 mRNA were found. The fact that increased IL‐6 mRNA levels were seen after both concentric and eccentric contractions indicates that the production of IL‐6 is not solely due to muscle damage, seen primarily after eccentric 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.

Changes in plasma concentrations of interleukin-6 and interleukin-1 receptor antagonists in response to adrenaline infusion in humans.

Abstract To investigate the possible role of adrenaline in the response of interleukin (IL)-6 and IL-1 receptor antagonists (ra) to extreme physiological conditions such as trauma and exercise, we examined the concentrations in the plasma of these cytokines during an adrenaline infusion. Given the fact that HIV infected patients have elevated levels of IL-6 in plasma, 12 HIV seropositive subjects and 6 HIV seronegative control subjects received a 1-h adrenaline infusion. Baseline concentrations of IL-6 and IL-1ra were higher in the HIV patients compared with the controls (P < 0.05 and P < 0.01, respectively), being most pronounced in the untreated subgroup of HIV infected patients (n=6). The plasma concentration of adrenaline had increased 24-fold after 15 min of adrenaline infusion. The plasma concentration of IL-6 had increased by two- to threefold after 45 min of adrenaline infusion (P < 0.01) and was still elevated 1 h after the infusion had ended (P < 0.001 and P < 0.05 in controls and HIV infected patients, respectively). The plasma concentration of IL-1ra had increased two- to threefold 1 h after ceasing the adrenaline infusion (P < 0.05 and P < 0.01 in controls and HIV infected patients, respectively). The relative increase in the cytokine levels was similar in controls and HIV infected patients. Thus, HIV infection did not influence the effect of adrenaline on IL-6 and IL-1ra. The present study supports the existence of a relationship between the plasma concentration of adrenaline and IL-6. It is possible that an increased adrenaline concentration in plasma induces a continued de novo synthesis of IL-6, thereby increasing plasma IL-6 in a time–dose dependent manner.

Exercise and immune function: effect of ageing and nutrition

Strenuous exercise is followed by lymphopenia, neutrophilia, impaired natural immunity, decreased lymphocyte proliferative responses to mitogens, a low level of secretory immunoglobulin A in saliva, but high circulating levels of pro- and anti-inflammatory cytokines. These exercise-induced immune changes may provide the physiological basis of altered resistance to infections. The mechanisms underlying exercise-induced immune changes are multifactorial and include neuroendocrinological and metabolic mechanisms. Nutritional supplementation with glutamine abolishes the exercise-induced decline in plasma glutamine, but does not influence post-exercise immune impairment. However, carbohydrate loading diminishes most exercise effects of cytokines, lymphocyte and neutrophils. The diminished neutrophilia and elastase (EC 3.4.21.37) responses to eccentric exercise in elderly subjects were enhanced to levels comparable with those of young subjects by fish oil or vitamin E supplements. However, although vitamin C supplementation may diminish the risk of contracting an infection after strenuous exercise, it is not obvious that this effect is linked to an effect of vitamin C on exercise-induced immune changes. In conclusion, it is premature to make recommendations regarding nutritional supplementation to avoid post-exercise impairment of the immune system.

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.