During "nondamaging" exercise, skeletal muscle markedly releases interleukin (IL)-6, and it has been suggested that one biological role of this phenomenon is to inhibit the production of tumor necrosis factor (TNF)- alpha, which is known to cause pathogenesis such as insulin resistance and atherosclerosis. To test this hypothesis, we performed three experiments in which eight healthy males either rested (CON), rode a bicycle for 3 h (EX), or were infused with recombinant human IL-6 (rhIL-6) for 3 h while they rested. After 2.5 h, the volunteers received a bolus of Escherichia coli lipopolysaccharide endotoxin (0.06 ng/kg) i.v. to induce low-grade inflammation. In CON, plasma TNF-alpha increased significantly in response to endotoxin. In contrast, during EX, which resulted in elevated IL-6, and rhIL-6, the endotoxin-induced increase in TNF-alpha was totally attenuated. In conclusion, physical exercise and rhIL-6 infusion at physiological concentrations inhibit endotoxin-induced TNF-alpha production in humans. Hence, these data provide the first experimental evidence that physical activity mediates antiinflammatory activity and suggest that the mechanism include IL-6, which is produced by and released from exercising muscles.

The aim of the present study was to examine whether IL-6 and TNF-α are expressed in, and released from, human skeletal muscle during exercise. We hypothesized that the skeletal muscle will release IL-6, but not TNF-α, during exercise because of previous observations that TNF-α negatively affects glucose uptake in skeletal muscle. Six healthy, male subjects performed 180 min of two-legged knee-extensor exercise. Muscle samples were obtained from the vastus lateralis of one limb. In addition, blood samples were obtained from a femoral artery and vein. Plasma was analyzed for IL-6 and TNF-α. We detected both IL-6 and TNF-α mRNA in resting muscle samples, and whereas IL-6 increased ( P < 0.05) ∼100-fold throughout exercise, no significant increase in TNF-α mRNA was observed. Arterial plasma TNF-α did not increase during exercise. Furthermore, there was no net release of TNF-α either before or during exercise. In contrast, IL-6 increased throughout exercise in arterial plasma, and a net IL-6 release from the contracting limb was observed after 120 min of exercise ( P < 0.05).

The present study was undertaken to examine the effect of prolonged running on monocyte intracellular cytokine production and plasma cytokine concentration. Blood samples were collected 1 h before, immediately after, 2 h after, and 24 h after a competitive marathon run. There was no change in the number of cells spontaneously producing tumor necrosis factor (TNF)-alpha; however, there was a decrease in the number of cells producing interleukin (IL)-1alpha and IL-6 (P < 0.01) postexercise. In contrast, there was an increase in the number of monocytes that responded to lipopolysaccharide stimulation by producing IL-1alpha, TNF-alpha, and IL-6 (P < 0.01) immediately and 2 h postexercise; however, these cells contained less cytokine (P < 0.05). Plasma IL-6, TNF-alpha, epinephrine, norepinephrine, and cortisol concentrations were markedly increased (P < 0.01) postexercise. These data demonstrate that circulating monocytes are not the source of elevated levels of plasma IL-6 and TNF-alpha after prolonged running. In addition, it is likely that stress hormones result in a decrease in the amount of cytokine produced by LPS-stimulated cells postexercise.