Constitutive pro- and anti-inflammatory cytokine and growth factor response to exercise in leukocytes

Abstract

Leukocytosis following exercise is a well-described phenomenon of stress/inflammatory activation in healthy humans. We hypothesized that, despite this increase in circulating inflammatory cells, exercise would paradoxically induce expression of both pro- and anti-inflammatory cytokines and growth factors within these cells. To test this hypothesis, 11 healthy adult men, 18-30 yr old, performed a 30-min bout of heavy cycling exercise; blood sampling was at baseline, end-exercise, and 60 min into recovery. The percentage of leukocytes positive for intracellular cytokines and growth factors and mean fluorescence intensity was obtained by flow cytometry. Proinflammatory cytokines (IL-1alpha, IL-2, IFN-gamma, and TNF-alpha), a pleiotropic cytokine (IL-6), and anti-inflammatory cytokines and growth factors [IL-4, IL-10, growth hormone (GH), and IGF-I] were examined. Median fluorescence intensity was not affected by exercise; however, we found a number of significant changes (P < 0.05 by mixed linear model and modified t-test) in the numbers of circulating cells positive for particular mediators. The pattern of expression reflected both pro- and anti-inflammatory functions. In T-helper lymphocytes, TNF-alpha, but also IL-6, and IL-4 were significantly increased. In monocytes, both IFN-gamma and IL-4 increased. B-lymphocytes positive for GH and IGF-I increased significantly. GH-positive granulocytes also significantly increased. Collectively, these observations indicate that exercise primes an array of pro- and anti-inflammatory and growth factor expression within circulating leukocytes, perhaps preparing the organism to effectively respond to a variety of stressors imposed by exercise.

Expression of intracellular cytokines, HSP72, and apoptosis in monocyte subsets during exertional heat stress in trained and untrained individuals

“…Therefore, it seems plausible that CD14 ϩ CD16 ϩ monocytes are responding to mild endotoxemia accompanying strenuous exercise (9,50) or EHS (68). A common finding when examining intracellular cytokine profiles with exercise, with or without hyperthermia, has been either no change or a slight reduction in the level of spontaneous TNF-␣ in cytokine-positive peripheral blood monocytes in trained (74,77,89) and untrained subjects (84), similar to the present study's responses in CD14 ϩϩ CD16 Ϫ monocytes. By contrast, Rhind et al (58) found corresponding increases in intracellular monocytic expression and circulating TNF-␣ during exhaustive exercise and subsequent cold exposure, changes that were suggested to be reflective of the inflammatory status of the cells before the exposure, or perhaps specific immune modulating influences accompanying exercise (58).…”

“…Early studies examining intracellular cytokine production have suggested that peripheral monocytes may not be a primary source of inflammatory cytokines released during strenuous exercise, despite well-documented increases in circulating TNF-␣ (74,77). This conclusion is also supported by more recent findings by Zaldivar et al (89) and Vassilakopoulous et al (84) suggesting that monocytes do not contribute significantly to augmented cytokine production following cycling exercise (30 -45 min, 75-80% V O 2peak ). Importantly, however, previous studies failed to distinguish between specific monocyte subsets, employing only single-color staining with CD14 ϩ (58, 84), CD33 ϩ (74 -77), or CD4 Dim (89) for monocyte identification, all of which are specific for the classic monocyte subset (5,12).…”

“…Many studies have reported changes in circulating proinflammatory cytokines during EHS (54,59,76), and the potential that these mediators originate from circulating leukocytes has been under considerable debate (21, 47, 58, 74 -76, 83). Several studies have examined monocytic protein content using a variety of methods including mRNA transcript expression (47, 83) and intracellular flow cytometry (58,74,76,77,84,89) in circulating monocytes, without distinction between subsets (21). We recently reported that increases in circulating TNF-␣ and endotoxin during EHS are accompanied by nuclear factor (NF)-B translocation in peripheral blood mononuclear cells, suggestive of peripheral blood inflammatory cell activation (68).…”

Serum from exercising humans suppresses t-cell cytokine production

“…Most investigations have focused on macrophage or monocyte cell lines and demonstrated that catecholamines like epinephrine inhibit cellular production of TNF-α (e.g., [36]). Using intracellular fluorescent staining and flow cytometry, we found that the numbers of t-cells positive for TNF-α increased following exercise, but not the mean fluorescent intensity [6]. Goebel and coworkers [37] using stimulated whole blood obtained from human participants after exercise and other psychological stressors showed that TNF-α production increased only with exercise but was blunted by isoproterenol infusion.…”

“…Circulating t-cell numbers and function are influenced by brief periods of exercise [6,7], and a number of mechanisms have been proposed to explain these effects. First, as noted, exercise alters circulating factors and mediators (e.g., lactate, IL-6, catecholamines, growth hormone) that can affect t-cells [8][9][10].…”