Physical exercise, inflammatory process and adaptive condition: an overview <s> ANTI-INflAmmATORy CyTOKINes <s> AbstractCytokines are soluble glycoproteins that are produced by and mediate communication between and within immune and nonimmune cells, organs and organ systems throughout the body. Pro- and anti-inflammatory mediators constitute the inflammatory cytokines, which are modulated by various stimuli, including physical activity, trauma and infection. Physical activity affects local and systemic cytokine production at different levels, often exhibiting striking similarity to the cytokine response to trauma and infection.The present review examines the cytokine response to short term exercise stress, with an emphasis on the balance between pro- and anti-inflammatory mechanisms and modulation of both innate and specific immune parameters through cytokine regulation. The effects of long term exercise on cytokine responses and the possible impact on various facets of the immune system are also discussed, with reference to both cross-sectional and longitudinal studies of exercise training. Finally, the validity of using exercise as a model for trauma and sepsis is scrutinised in the light of physiological changes, symptomatology and outcome, and limitations of the model are addressed.Further studies, examining the effect of exercise, trauma and infection on novel cytokines and cytokine systems are needed to elucidate the significance of cytokine regulation by physical activity and, more importantly, to clarify the health implications of short and long term physical activity with respect to overall immune function and resistance to infection. <s> BIB001 </s> Physical exercise, inflammatory process and adaptive condition: an overview <s> ANTI-INflAmmATORy CyTOKINes <s> To determine whether the cytokine interleukin (IL)-6 induces heat shock protein (HSP) 72 gene expression in skeletal muscle, 18 healthy, young men had either a high dose of IL-6 (HiIL-6; n=6), low dose IL-6 (LoIL-6; n=6), or saline (CON; n=6) infused into one femoral artery for 3h. Muscle biopsies were obtained from the vastus lateralis of the infusion limb and samples were analyzed for HSP72 mRNA. In addition, blood samples were collected from the femoral vein of the infusion limb and analyzed for plasma IL-6. In CON, femoral vein IL-6 concentration remained at basal levels throughout the experiment but in both HiIL-6 and LoIL-6, femoral vein IL-6 concentrations were markedly elevated (P<0.05). HSP72 gene expression did not increase above resting levels in CON. In contrast, in both HiIL-6 and LoIL-6, HSP72 mRNA increased (P<0.05) 2.5- and 2.3-fold, respectively after 30min of infusion and remained elevated (P<0.05) for 24h following infusion. These data demonstrate that IL-6 can rapidly induce HSP72 gene expression in human skeletal muscle. <s> BIB002 </s> Physical exercise, inflammatory process and adaptive condition: an overview <s> ANTI-INflAmmATORy CyTOKINes <s> Regular exercise offers protection against all-cause mortality, primarily by protection against cardiovascular disease and Type 2 diabetes mellitus. The latter disorders have been associated with chronic low-grade systemic inflammation reflected by a two- to threefold elevated level of several cytokines. Adipose tissue contributes to the production of TNF-α, which is reflected by elevated levels of soluble TNF-α receptors, IL-6, IL-1 receptor antagonist, and C-reactive protein. We suggest that TNF-α rather than IL-6 is the driver behind insulin resistance and dyslipidemia and that IL-6 is a marker of the metabolic syndrome, rather than a cause. During exercise, IL-6 is produced by muscle fibers via a TNF-independent pathway. IL-6 stimulates the appearance in the circulation of other anti-inflammatory cytokines such as IL-1ra and IL-10 and inhibits the production of the proinflammatory cytokine TNF-α. In addition, IL-6 enhances lipid turnover, stimulating lipolysis as well as fat oxidation. We suggest that regular exercise induces suppression of TNF-α and thereby offers protection against TNF-α-induced insulin resistance. Recently, IL-6 was introduced as the first myokine, defined as a cytokine that is produced and released by contracting skeletal muscle fibers, exerting its effects in other organs of the body. Here we suggest that myokines may be involved in mediating the health-beneficial effects of exercise and that these in particular are involved in the protection against chronic diseases associated with low-grade inflammation such as diabetes and cardiovascular diseases. <s> BIB003 </s> Physical exercise, inflammatory process and adaptive condition: an overview <s> ANTI-INflAmmATORy CyTOKINes <s> A review of the systemic acute phase reaction with major cytokines involved, and the hepatic metabolic changes, negative and positive acute phase proteins (APPs) with function and associated pathology is given. It appears that APPs represent appropriate analytes for assessment of animal health. Whereas they represent non-specific markers as biological effect reactants, they can be used for assessing nutritional deficits and reactive processes, especially when positive and negative acute phase variables are combined in an index. When such acute phase index is applied to separate healthy animals from animals with some disease, much better results are obtained than with single analytes and statistically acceptable results for culling individual animals may be reached. Unfortunately at present no cheap, comprehensive and easy to use system is available for assessing various acute phase proteins in serum or blood samples at the same time. Protein microarray or fluid phase microchip technology may satisfy this need; and permit simultaneous analysis of numerous analytes in the same small volume sample and enable integration of information derived from systemic reactivity and nutrition with disease specific variables. Applying such technology may help to solve health problems in various countries not only in animal husbandry but also in human populations. <s> BIB004 </s> Physical exercise, inflammatory process and adaptive condition: an overview <s> ANTI-INflAmmATORy CyTOKINes <s> PURPOSE OF REVIEW ::: To evaluate the effects of exercise on immune function in relation to infection susceptibility. ::: ::: ::: RECENT FINDINGS ::: Postexercise immune function depression is most pronounced when exercise is continuous, prolonged, of moderate to high intensity and performed without food intake. Periods of intensified training that result in overreaching have been shown to chronically depress immune function, with leukocyte functions measured at rest still depressed 24 h after the last exercise bout. Several studies indicate that the incidence of symptoms of upper respiratory tract illness is increased in the days following prolonged strenuous endurance events and it has been generally assumed that this is due to the temporary exercise-induced depression of immune function. More recently it has been proposed that at least some of these symptoms are attributable to inflammation of the upper respiratory tract rather than to infectious episodes. ::: ::: ::: SUMMARY ::: Although elite athletes are not clinically immune deficient, it is possible that the combined effects of small changes in several immune parameters may compromise resistance to common minor illnesses. Although it is possible that immune depression linked with prolonged intensive training may determine susceptibility to infection, convincing evidence of a cause and effect relationship remains elusive. <s> BIB005 </s> Physical exercise, inflammatory process and adaptive condition: an overview <s> ANTI-INflAmmATORy CyTOKINes <s> Skeletal muscles adapt to increasing workload by augmenting their fiber size, through mechanisms that are poorly understood. This study identifies the cytokine interleukin-6 (IL-6) as an essential regulator of satellite cell (muscle stem cell)-mediated hypertrophic muscle growth. IL-6 is locally and transiently produced by growing myofibers and associated satellite cells, and genetic loss of IL-6 blunted muscle hypertrophy in vivo. IL-6 deficiency abrogated satellite cell proliferation and myonuclear accretion in the preexisting myofiber by impairing STAT3 activation and expression of its target gene cyclin D1. The growth defect was indeed muscle cell intrinsic, since IL-6 loss also affected satellite cell behavior in vitro, in a STAT3-dependent manner. Myotube-produced IL-6 further stimulated cell proliferation in a paracrine fashion. These findings unveil a role for IL-6 in hypertrophic muscle growth and provide mechanistic evidence for the contribution of satellite cells to this process. <s> BIB006
IL-6 has already been called the exercise factor, in addition to Interleukin 8 (IL-8) and Interleukin 15 (IL-15) cytokines BIB003 . The regulatory activity of the inflammatory process of IL-6 has been considered in literature as the main agent regulating the acute phase response in exercise. This cytokine is produced in higher concentrations in skeletal muscle tissue, in leukocytes and in endothelial cells through signaling of pro-inflammatory cytokines and ROS, and its secretion is related to intensity, duration and the amount of muscle mass involved in physical exercise BIB003 . The anti-inflammatory activities of IL-6 are diverse and include inhibitory effects on the production and secretion of TNF-a, stimulating the synthesis of anti-inflammatory cytokines such as the antagonist receptor of Interleukin-1 (IL-1ra) and Interleukin-10 (IL-10), and also stimulating the release of soluble receptors for TNF-a BIB001 BIB003 . Among some specific roles played by IL-1ra and IL-10, the blockade in presentation of antigens by macrophages, the inhibition in the production of IL-1β, IL-6, TNF-a and chemokines by macrophages and lymphocytes, and thus the completion of the inflammatory response stand out BIB001 BIB003 . The hepatic synthesis of acute phase proteins is also controlled by IL-6 BIB004 , which also has hypothalamic receptors that activate the hypothalamicpituitary-adrenal axis and increase the secretion of cortisol by the adrenal cortex 3 . IL-6 activates the hepatic glycogenolysis BIB003 and lipolysis in adipose tissue via activation of the AMPdependent kinase (AMPK). Increasing the oxidation rate of fatty acids is important to provide energy for tissue synthesis and repair processes BIB003 . IL-6 also controls the oxidative stress condition in the injured tissue through induction in expression of heat shock proteins (HSPs) in both skeletal muscle tissue and immune cells BIB002 , and regulates the migration of satellite cells in order to promote muscle tissue hypertrophy BIB006 . Finally, IL-6, along with Interleukin 4 (IL-4), Interleukin 5 (IL-5), IL-10, Interleukin 13 (IL-13) and IL-1ra seems to drive the inflammatory response pattern to an increased antibody production and a marked activation of eosinophils BIB005 .