Exercise and the Immune System: Regulation, Integration, and Adaptation

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)alpha, interleukin (IL)-1beta, 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-1beta, TNFalpha, 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 TNFalpha and IL-1beta 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.

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-1beta and tumour necrosis factor (TNF)-alpha 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-1beta mRNA were found in one muscle and four BMNC samples after exercise. TNF-alpha 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.

Activation in lectin-free interleukin 2 (IL-2) containing supernatants of peripheral blood mononuclear leukocytes (PBL) from cancer patients or normal individuals resulted in expression of cytotoxicity toward 20 of 21 natural killer (NK)-resistant fresh solid tumor cells tested. Fresh solid tumor cells were resistant to NK-mediated lysis in 10 autologous patients' PBL-tumor interactions, and from 17 normal individuals tested against 13 allogeneic fresh tumors. Culture of PBL in IL-2 for 2-3 d was required for the lymphokine activated killers (LAK) to be expressed, and lytic activity toward a variety of NK- resistant fresh and cultured tumor targets developed in parallel. Autologous IL-2 was functional in LAK activation, as well as interferon- depleted IL-2 preparations. Irradiation of responder PBL before culture in IL-2 prevented LAK development. Precursors of LAK were present in PBL depleted of adherent cells and in NK-void thoracic duct lymphocytes, suggesting that the precursor is neither a monocyte nor an NK cell. LAK effectors expressed the serologically defined T cell markers of OKT.3, Leu-1, and 4F2, but did not express the monocyte/NK marker OKM-1. Lysis of autologous fresh solid tumors by LAK from cancer patients' PBL was demonstrated in 85% of the patient-fresh tumor combinations. Our data present evidence that the LAK system is a phenomenon distinct from either NK or CTL systems that probably accounts for a large number of reported nonclassical cytotoxicities. The biological role of LAK cells is not yet known, although it is suggested that these cells may be functional in immune surveillance against human solid tumors.