Hindawi Publishing Corporation Mediators of Inflammation Volume 2008, Article ID 109502, 6 pages doi:10.

1155/2008/109502

Review Article Exercise as a Mean to Control Low-Grade Systemic Inflammation
Neha Mathur and Bente Klarlund Pedersen
The Centre of Inflammation and Metabolism (CIM), Department of Infectious Diseases and CMRC, Rigshospitalet, Faculty of Health Sciences, University of Copenhagen, Blegdamsvej 9, 2100 Copenhagen, Denmark Correspondence should be addressed to Bente Klarlund Pedersen, bkp@rh.dk Received 29 July 2008; Accepted 11 November 2008 Recommended by Eric Morand Chronic noncommunicable diseases (CNCDs), which include cardiovascular disease, some cancers, for example, colon cancer, breast cancer, and type 2 diabetes, are reaching epidemic proportions worldwide. It has now become clear that low-grade chronic inflammation is a key player in the pathogenesis of most CNCDs. Given that regular exercise offers protection against all causes of mortality, primarily by protection against atherosclerosis and insulin resistance, we suggest that exercise may exert some of its beneficial health effects by inducing anti-inflammatory actions. Recently, IL-6 was introduced as the first myokine, defined as a cytokine, which is produced and released by contracting skeletal muscle fibres, exerting its effects in other organs of the body. We suggest that skeletal muscle is an endocrine organ and that myokines may be involved in mediating the beneficial effects against CNCDs associated with low-grade inflammation. Copyright © 2008 N. Mathur and B. K. Pedersen. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

1.

INTRODUCTION

Chronic noncommunicable diseases (CNCDs) which include cardiovascular conditions (mainly heart diseases and stroke), some cancers, chronic respiratory conditions, and type 2 diabetes, affect people of all nationalities and classes and are reaching epidemic proportions worldwide [1–4]. CNCDs cause the greatest global share of death and disability, accounting for around 60% of all deaths worldwide. Approximately, 80% of chronic-disease deaths occur in low- and middle-income countries and account for 44% of premature deaths worldwide. It is estimated that the number of deaths from these diseases is double the number of deaths that result from a combination of infectious diseases (including HIV/AIDS, tuberculosis, and malaria), maternal and perinatal conditions, and nutritional deficiencies [1]. From a historical perspective, inflammation has been considered as the natural host response to an acute infectious episode, whereas chronic inflammation has been considered a sign of chronic infection. It has now become clear that low-grade chronic inflammation is a key player in the pathogenesis of most NCDCs. There has been an increasing

appreciation of the role of inflammation both in the pathogenesis of atherosclerosis [5, 6] and as a key factor in insulin resistance [7]. Low-grade chronic inflammation is characterized by increased systemic levels of some cytokines and C-reactive protein (CRP) and a number of studies have confirmed an association between low-grade systemic inflammation on one hand and atherosclerosis and type 2 diabetes on the other [8]. Physical inactivity has been identified as a stronger predictor of these chronic diseases than risk factors such as hypertension, hyperlipidemia, diabetes, and obesity for all-cause mortality [9]. Moreover, regular physical activity appears to protect against premature death independent of obesity [10, 11]. Regular physical activity offers protection against, and may be useful as a treatment for a wide variety of, chronic diseases associated with low-grade inflammation [12]. The protective effects of regular exercise against diseases such as cardiovascular disease, type 2 diabetes, colon cancer, and breast cancer have been reviewed extensively [13–16]. Recent findings demonstrate that physical activity induces an increase in the systemic levels of a number of cytokines with anti-inflammatory properties [8, 17] and

THE DIRECT METABOLIC ROLES OF TNF Growing evidence suggests that TNF-α plays a direct role in metabolic syndrome. The discovery of contracting muscle as a cytokineproducing organ opens a new paradigm. The systemic response known as the acute-phase response includes the production of a large number of hepatocyte-derived acute phase proteins. and IL-6 into laboratory animals or humans [8. lifestyle factors such as smoking and obesity. 22]. 52] and in mice [53]. TNF-α directly impaired glucose uptake and metabolism by altering insulin signal transduction. Interestingly. In humans. we found that TNFα induces insulin resistance in skeletal muscle. lower limb. is the main source of the circulating TNF-α [37–39]. and it is likely that adipose tissue. The initial cytokines as they appear in the circulation in relation to an acute infection consist of the following: TNF-α. 21]. Thus. including IL-6. Moreover. excessive concentrations of TNFalpha negatively regulate insulin signalling and whole-body glucose uptake in humans. circulating IL-6 levels may [46] or may not [47] be associated with insulin resistance. and CRP has emerged as a particularly stronger independent risk factor for cardiovascular disease than the low-density lipoprotein cholesterol level [13. the cytokines and cytokines inhibitors will increase [20]. and is therefore probably not relevant to human physiology. together with increased risk of cardiovascular disease and type 2 diabetes [22. TNF-α induces insulin resistance through increased serine phosphorylationof insulin receptor substrate-1 (IRS-1). evidence for a direct role of TNF-α in insulin resistance in humans in vivo has been obtained [44]. 34]. which produces and releases cytokines (also called myokines) [18. Despite the fact that the changes in acute-phase reactants are much smaller than those in acute infections. the chronicity of low-grade inflammation is strongly associated with increasing age. 19]. 25. skeletal muscle is an endocrine organ that. and soluble TNFα-receptors (sTNF-R). In the latter case. In cultured cells. When diabetes patients were given an rhIL-6 infusion. 3. 30]. 49]. 40]. and IL-10. When TNF-α was infused into healthy humans. The findings with regard to an effect of TNF on both glucose and fat metabolism provide a direct molecular link between low-grade systemic inflammation and the metabolic syndrome [44. by contraction. plasma concentrations of insulin decreased to levels comparable with that in age and BMI (body mass index)-matched healthy controls. These signalling effects were associated with impaired phosphorylation of Akt substrate 160. CHRONIC LOW-GRADE SYSTEMIC INFLAMMATION AND ITS CONSEQUENCES Mediators of Inflammation insulin resistance. IL-6. However. indicating that the IL-6 enhanced insulin sensitivity [50]. and the acute phase reactant C-reactive protein (CRP) [13. Plasma concentrations of IL-6 [31] and TNF-α have been shown to predict the risk of myocardial infarction in several studies [32]. The response can be mimicked by the injection of the cytokines TNF-α. natural occurring cytokine antagonists.to 3-fold elevation in the systemic concentrations of proinflammatory and anti-inflammatory cytokines.2 skeletal muscle has recently been identified as an endocrine organ. 43]. 4. which subsequently converts IRS-1 to an inhibitor of insulin receptor tyrosinekinase activity [41]. Infusion of recombinant human (rh) IL-6 into resting healthy humans does not impair whole body. After adjustment for multiple confounders. 45]. a number of studies indicate that elevated TNF-α is not secondary to the pathological conditions associated with With regard to IL-6. the IL-6 dose applied in the latter studies was supraphysiological. which may influence metabolism and modify cytokine production in tissue and organs. THE DIRECT METABOLIC ROLES OF IL-6 In response to an acute infection or trauma. IL-1β. without an effect on endogenous glucose production. stimulates the production and release of myokines. 2. and c-Jun NH(2)-terminal kinase. it was recently demonstrated that TNF-alpha infusion increases whole-body lipolysis by 40% with a concomitant increase in FFA clearance. In vitro studies demonstrate that IL-6 can induce insulin resistance in isolated 3T3-L1 adipocytes [51. concomitant with increased serine and reduced tyrosine phosphorylation of insulin receptor substrate-1. the stimuli for the cytokine production are not known. extracellular signal-regulated kinase-1/2. accumulating data suggest that IL-6 enhances glucose uptake in myocytes [54–57]. IL-1β. such as C-reactive protein (CRP) that is known to be a sensitive marker of systemic inflammation. IL-1 receptor antagonist (IL-1ra). obesity. but with no changes in skeletal muscle FFA uptake. Patients with diabetes demonstrate high expression of TNF-α in skeletal muscle and in plasma. IL-6 knockout mice develop impaired glucose tolerance that is reverted by IL-6. Thus. or oxidation [45]. but it is assumed that the origin of TNF in chronic low-grade systemic inflammation is mainly the adipose tissue [23–26]. . or subcutaneous adipose tissue glucose uptake or endogenous glucose production [48. TNF-α has been shown to have a direct (insulinindependent) effecton S6K and ERK-1/2 in cultured cells [42. via direct effect of TNF-α on insulin signaling [35. Chronic low-grade systemic inflammation has been characterized by a 2. TNF-alpha infusion increased phosphorylation of p70 S6 kinase. 27–29]. and cardiovascular disease are related to a state of low-grade systemic inflammation [7. Type 2 diabetes. high plasma TNF concentrations are associated with insulin resistance [40]. which produces TNF-α. release. 36]. Thus. the most proximal step identified in the canonical insulin signalling cascade regulating GLUT4 translocation and glucose uptake. but that TNF-α plays a direct pathogenic role in glucose metabolism [29. In addition. its role in insulin resistance is highly controversial. 33.

49]. 5. 75. Taken together. or any adverse effects in healthy individuals as well as patients with type 2 diabetes [49. In addition. in elderly people [76. and appears to be the primary inducer of the hepatocyte-derived acute-phase proteins. many of which have anti-inflammatory properties. ANTI-INFLAMMATORY EFFECTS OF IL-6 3 Of note. The exercise-induced increase in plasma IL-6 levels is followed by increased circulating levels of well-known antiinflammatory cytokines such as IL-1ra and IL-10 [28. 50. In resting subjects. we demonstrated that IL-6 increased the glucose infusion rate [56] and glucose oxidation without affecting the suppression of endogenous glucose production during a hyperinsulinemic euglycemic clamp in healthy humans. when the mice were treated with IL-6. and declines in the postexercise period [60–62]. and the appearance of IL-6 in the circulation is by far the most marked and its appearance precedes that of the other cytokines. Pedersen A number of studies indicate that IL-6 enhances lipolysis. together with cell culture experiments demonstrating that IL-6 alone markedly increases both lipolysis and fat oxidation. Data suggest that IL-6 exerts inhibitory effects on TNF-α and IL-1 production. there was a significant decrease in body fat mass in the IL-6 knockout but not in the wild-type mice. the finding in longitudinal studies that regular training induces a reduction in CRP level suggests that the physical activity as such may suppress systemic lowgrade inflammation [74. To study whether acute exercise induces a true antiinflammatory response. 64. CYTOKINE RESPONSES TO EXERCISE Though an acute bout of physical activity is accompanied by responses that in many respects are similar to those induced by infection and sepsis. Given the different biological profiles of TNF-α and IL-6.N. 60. and given that TNF-α can trigger IL-6 release. and in patients with intermittent claudication [78]. ANTI-INFLAMMATORY EFFECTS OF EXERCISE A number of studies suggest that regular exercise has antiinflammatory effects. 58]. in general do not increase with exercise. indicating that circulating IL-6 is involved in the regulation of TNF-α levels. there are some important differences in the cytokine response to exercise from that elicited by severe infection [27. Recently. IL-6 is the first cytokine present in the circulation during exercise. It has been suggested that IL-6 promotes insulin resistance due to the observation that plasma IL-6 is often elevated in patients with metabolic disease [70]. 77]. From a simplistic physiological point of view. identify IL-6 as a novel lipolytic factor. 6. 63]. 60. Wallenius et al. Moreover. 80]. The IL-6 response to exercise has recently been reviewed [13. intensity. Cross-sectional studies demonstrate an association between physical inactivity and low-grade systemic inflammation in healthy subjects [71–75]. it seems paradoxical that working muscle would release a factor that inhibits insulin signalling when insulin sensitivity is enhanced in the immediate postexercise period [28]. a model of “low-grade inflammation” was established in which we injected a low dose of Escherichia coli endotoxin to healthy volunteers. In addition. 62]. although data also suggest that IL-6 and IL-6regulated acute phase proteins are anti-inflammatory and immunosuppressive. 60. The striking difference between exercise and sepsis with regard to cytokine responses is that the classical proinflammatory cytokines. Furthermore. K. followed by an increase in IL-1ra and IL-10. 18. 58]. In addition. 18. and may negatively regulate the acutephase response [20]. endotoxin induced a 2to 3-fold increase in circulating levels of TNF-α. insulin. it is apparent that in vivo studies in humans provide little or no evidence that IL-6 is a direct player in the metabolic syndrome. 2002 demonstrated that IL-6 deficient mice developed mature-onset obesity and insulin resistance. one theory holds that it is the adipose tissue-derived TNF-α that actually is the “driver” behind the metabolic syndrome [36] and that locally produced TNF-α causes increased systemic levels of IL-6. 79. and levels of TNF-α are markedly elevated in anti-IL-6-treated mice and in IL-6-deficient knockout mice [67. glucagon. In contrast. TNF-α and IL-1β. Consistent with this idea. 59]. but not IL-1β and TNF-α. exercise provokes an increase primarily in IL-6. A marked increase in circulating levels of IL-6 after exercise without muscle damage has been a remarkably consistent finding. Mathur and B. 8. it has been demonstrated that the IL-6 protein is expressed in contracting muscle fibres and that IL-6 is released from skeletal muscle during exercise [28]. These findings. A number of studies have demonstrated that working muscle produces IL-6. Typically. The level of circulating IL-6 increases in an exponential fashion (up to 100 fold) in response to exercise. rhIL-6 infusion inhibits the endotoxininduced increase in circulating levels of TNF-α in healthy humans [69]. 65]. 68]. IL-6 stimulates the release of soluble TNF-α receptors. who had been randomized to either rest or exercise prior to endotoxin administration. Infusion of rhIL-6 into healthy humans to obtain physiological concentrations of IL-6 increased lipolysis in the absence of hypertriacylglyceridemia or changes in catecholamines. 48]. Taken together. Interleukin-6 is most often classified as a proinflammatory cytokine. and muscle mass involved in the mechanical work [13. Thus muscle biopsies obtained before and after exercise in humans and rats demonstrate very little IL-6 mRNA in resting muscle. The magnitude by which plasma IL-6 increases is related to exercise duration. when the subjects performed 3 hours of ergometer cycling . but up to a 100fold increase in exercising skeletal muscle [18. IL-6 inhibits lipopolysaccharide (LPS)-induced TNF-α production both in cultured human monocytes and in the human monocytic line U937 [66]. TNF/IL-6-INTERACTION 7. 61]. only IL-6 appears to induce fat oxidation [19. whereas it is known that both TNF-α and IL-6 induce lipolysis [40. as well as fat oxidation [50.

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