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It is known that interleukin (IL)-12 p70 promotes the differentiation of type-1 helper T (Th1) cells, which produce type-1 cytokines such as IL-2 and interferon (IFN), thereby supporting cellular immunity, whereas IL-12 p40 acts as an antagonist of IL-12 p70. In contrast, IL-4 and IL-6 promote the differentiation of Th2 cells, which produce type-2 cytokines IL-4, IL-6 and IL-10, induce humoral immunity and are involved in allergic reactions. Exhaustive exercise causes the suppression of T lymphocyte activity while asthmatic and allergic diseases are subclinically more prevalent in athletes. One of the mechanisms behind these observations might be a lower type-1 and higher type-2 cytokine balance, which we previously demonstrated to occur after exhaustive exercise. In the present study, we investigated the type-1/type-2 cytokine balance by measuring plasma concentrations of IL-2, IL-4, IL-5, IL-10, tumor necrosis factor (TNF)-alpha and IFN-gamma with microparticle-based flow cytometric technology. IL-5, IL-6 and IL-13 were measured by enzyme-linked immunosorbent assay (ELISA). IL-12 p40 and p70 were measured separately, also by ELISA. Plasma IL-12 p40 concentration rose significantly after maximal exercise and to an even greater extent after a marathon race. Conversely, plasma IL-12 p70 could not be detected even using two different assays. The marathon race caused a marked increase in the plasma concentrations of IL-6 and IL-10. Their responses were correlated (r = 0.78, p < 0.01), indicating that IL-6 is an inducer of IL-10, and may partly induce the type-1 < type-2 cytokine balance. With the exception of one study involving maximal exercise, other studies have failed to show any change in circulating IL-12 concentration with exercise. The present study demonstrated that IL-12 p40 was present in excess of p70 especially after exercise. This may be one of the mechanisms behind several phenomena including cellular immunosuppression, an increase in the relative proportion of type-2 cytokines following exhaustive exercise, and the higher incidence of infections and allergic disorders in regularly exercising endurance athletes.

It has been documented that strenuous exercise not only induces pyrogenesis but also elicits mobilization and functional augmentation of neutrophils and monocytes whereas it suppresses cellular immunity leading to increased susceptibility to infections. As mediators of these phenomena, cytokines released into the circulation have been a recent focus of attention. Indeed, there are as many as one hundred original reports concerning exercise and cytokines, and half of them have been published in rapid succession from 2000, resulting in a tremendous accumulation of new knowledge within such a short term. The first aim of this review is to comprehensively summarize previous studies on systemic cytokine kinetics following exercise, with a special focus on reproducibility and quantitative comparison in human studies using specific immunoassays. Although tumor necrosis factor (TNF)-alpha and interleukin (IL)-1 beta have traditionally been understood to be the main inducer cytokines of acute phase reactions, the majority of studies have shown that the circulating concentration of these cytokines is either unchanged following exercise, or exhibits relatively small, delayed increments. Plasma interferon (IFN)-alpha and IFN-gamma do not appear to change following exercise, whereas IL-2 decreases after endurance exercise. The small changes of these proinflammatory and immunomodulatory cytokines could well be mediated by anti-inflammatory cytokines such as IL-1 receptor antagonist (IL-1ra), IL-6 and IL-10 and cytokine inhibitors (cortisol, prostaglandin E2 and soluble receptors against TNF and IL-2), which are known to increase markedly in the circulation following endurance exercise. Moreover, it has been recently demonstrated that endurance exercise induces systemic release of granulocyte colony-stimulating factor (G-CSF), macrophage CSF (M-CSF), IL-8 and monocyte chemotactic protein 1 (MCP-1). Although the majority of available data have been obtained following prolonged exercise, it remains to be elucidated whether short-duration intensive exercise also causes rapid systemic cytokine release. In addition, there have been few studies that have simultaneously compared the extent of each cytokine response to exercise from a wider perspective. The second aim of this study was to examine possible changes of not only plasma but also urine concentrations of a broad spectrum of cytokines (16 kinds) following maximal exercise, including the time course of recovery. Although plasma TNF-alpha could not be detected throughout, it was present in urine 2 h after exercise. Plasma IL-1 beta rose significantly 2 h after exercise, but plasma IL-1 ra increased more rapidly and markedly than IL-1 beta, thus IL-1 bioactivity should be blocked at least in the circulation. Although there was only a trend toward increased plasma IL-6 concentrations after exercise, urine IL-6 rose significantly 1 h after exercise, indicating that IL-6 was released systemically but eliminated rapidly into the urine. Furthermore, it is shown for the first time that plasma and urine IL-4 concentrations were significantly elevated 2 h after exercise. Therefore, it is possible that anti-inflammatory cytokines might be released into the circulation as a regulatory mode of the cytokine network for adaptation against systemic inflammatory stress. Additionally, we have demonstrated that plasma concentrations of G-CSF, granulocytemacrophage CSF (GM-CSF), M-CSF, IL-8 and MCP-1 increased immediately after short-duration exercise and that the urine concentrations of these cytokines were much more pronounced than the changes observed in plasma. In conclusion, cytokines that are considered to induce systemic bioactivity following exercise are not only anti-inflammatory cytokines but also colony-stimulating factors and chemokines, which were secreted in an earlier phase of exercise without the kinetic involvement of traditional proinflammatory cytokines. Although the wider physiological and pathological implications are still not clearly understood, these cytokine kinetics may partly explain suppressed cell-mediated immunity and increased allergic reactions derived from a lower type-1 to type-2 cytokine ratio, along with mobilization and functional augmentation of neutrophils and monocytes. The sources and stimuli of cytokine production are not fully elucidated at present, but several hypotheses based on recent experimental evidence are discussed in this review herein.