Exercise and the cytokine balance: A paediatric perspective

In the last five years, a wealth of scientific literature regarding cytokine responses to exercise has emerged. Perhaps one of the most exciting observations is that skeletal muscle expresses a number of cytokines in response to contraction (see reviews by Petersen & Pedersen, 2005 and Bruunsgaard, 2005). Accordingly, these observations began to remodel the way some researchers interpreted exercise-induced changes in cytokines, and interleukin-6 (IL-6) in particular. Because IL-6 appears to be the most responsive cytokine to exercise and because of its metabolic and anti-inflammatory effects, it has been argued that this cytokine may help mediate the numerous health benefits of regular exercise (Petersen & Pedersen, 2005, Bruunsgaard, 2005). In contrast, the pro-inflammatory cytokine tumour necrosis factor-a (TNF-a) has been assigned a number of negative qualities, such as inhibition of protein synthesis (e.g. Frost, Lang, & Gelato, 1997) and reduction in insulin sensitivity (e.g. Plomgaard et al., 2005); these effects are more likely to be detrimental to overall health. Mounting evidence also suggests that IL-6 can inhibit TNF-a production under inflammatory conditions (Starkie, Ostrowski, Jauffred, Febbraio, & Pedersen, 2003). Consequently, the systemic balance between these two cytokines, and not necessarily their absolute concentrations, may provide important insight into the inflammatory environment in health and disease. In this editorial, I propose that the ratio of IL-6 to TNF-a might be considered a useful ‘‘anti-inflammatory index’’. This anti-inflammatory index may be of particular significance from a paediatric perspective. It is well documented that TNF-a inhibits muscle protein synthesis (e.g., Frost et al., 1997) and bone formation (e.g. Bertolini, Nedwin, Bringman, Smith, & Mundy, 1986). Given this antagonism between inflammation and growth, a low anti-inflammatory index (i.e. high TNF-a relative to IL-6) would be considered detrimental to optimal tissue development during childhood. But what happens to the cytokine balance in children when they exercise? Compared with adults, children experience an approximate six-fold smaller exercise-induced increase in IL-6 and an approximate four-fold smaller exercise-induced increase in TNF-a (see review by Timmons, in press). Moreover, the anti-inflammatory index remains more than two-fold higher in the children (*3.3) than in adults (*1.4) even in the face of physiological stress (Timmons, in press). Why, then, should growing children exhibit such responses? One possible explanation is that the growing child possesses inherent mechanisms to alleviate inflammatory-related responses to physiological stress. This ‘‘inflammatory protection’’, indicated by a high anti-inflammatory index, would allow for the anabolic effects of exercise (e.g. stimulation of muscle and bone growth) to take priority, thus reflecting an overall positive response from a growth perspective. Indeed, there is strong evidence that enhanced physical activity during childhood can promote skeletal muscle and bone tissue development above that which would be expected due to normal growth alone (see Eliakim, 2004). If children experienced exercise-induced inflammatory responses to the same degree as those of adults, would they achieve similar anabolic benefits? The potential health implications of the antiinflammatory index are further magnified when one considers that paediatric conditions associated with reduced growth rates (e.g. juvenile arthritis and cystic fibrosis) are also characterized by chronic levels of inflammation. If one surveys the literature and calculates the anti-inflammatory index for children with juvenile arthritis (e.g. Ou et al., 2002, Shahin et al., 2002) and cystic fibrosis (e.g. Colombo et al., 2005, Cunningham, McColm, Mallinson, Boyd, & Marshal, 2003), they would find much lower values (40.5), suggesting that the cytokine balance may be of particular significance in global processes of growth. While these observations revolve solely around IL-6 and TNF-a, there are, obviously, numerous other cytokines and growth factors involved in tissue adaptation to injury, stress, and exercise, and I am under no illusion that all secrets lay in an anti-inflammatory index. However, by understanding how factors such as disease and exercise influence this cytokine (im)balance, we may be better equipped to improve children’s health. The role of cytokines in human health has moved far beyond solely immune-modulating effects. Health disorders such as obesity, Type 2 diabetes mellitus (T2DM), and cardiovascular disease possess a strong immune link. Physical inactivity among Journal of Sports Sciences, January 2006; 24(1): 1 – 2