Introduction

It is now well established that chronic inflammation, indicated by modest increased levels in cytokines, contributes to the development and progression of chronic noncommunicable diseases such as type 2 diabetes mellitus (T2DM) and cardiovascular disease (CVD) 1-8. Evidence suggests that chronic inflammation is involved in the pathogenesis of, for example, insulin resistance, pancreatic cell death, atherosclerosis, neurodegeneration and tumour growth 9.

Persistent systemic inflammation is also a key symptom in most inflammatory rheumatic diseases 10, 11 and may highly contribute to the substantially increased cardiovascular risk 12 and associated comorbidities (i.e. muscle waste, anaemia, insulin resistance, dyslipidaemia and accelerated atherosclerosis) in these diseases 11.

A substantial number of both longitudinal and cross‐sectional studies in healthy and diseased people have demonstrated that markers of inflammation are reduced following longer‐term behavioural changes involving both reduced energy intake and increased physical activity 11, 13-19, and it is likely that the anti‐inflammatory effects of regular exercise contribute to mediate the health beneficial consequences of exercise. Physical activity represents a cornerstone in the primary prevention of at least 35 chronic conditions 20, and exercise has a potential role as medicine in many diseases 21.

This review discusses the mechanisms whereby exercise training may mediate anti‐inflammation and the interpretation of such findings in the management of patients with type 2 diabetes, ischaemic heart disease and heart failure.

Anti‐inflammatory effects of acute exercise Skeletal muscle is able to communicate with other organs via secretory peptides, the so‐called myokines 22-26. The muscle secretome consists of several hundred secreted peptides, which provides a conceptual basis for understanding how muscles communicate with other organs. As previously reviewed 11, some myokines are involved in muscle hypertrophy. These include leukaemia inhibitory factor (LIF), IL‐4, IL‐6, IL‐7 and IL‐15. Myostatin inhibits muscle hypertrophy, and exercise provokes the release of a myostatin inhibitor, follistatin, from the liver. BDNF and IL‐6 are involved in AMPK‐mediated fat oxidation; IL‐6 stimulates lipolysis and IL‐15 stimulates in particular lipolysis of visceral fat. IL‐6 is involved in glucose and lipid metabolism. Furthermore, IL‐6 stimulates cortisol production and hence neutrocytosis and lymphopenia. IL‐8 and CXCL‐1 may promote angiogenesis. IGF‐1, FGF‐2 and TGF‐β are involved in bone formation, and follistatin‐related protein 1 improves endothelial function and revascularization of ischaemic vessels, whereas irisin and meteorin‐like play a role in ‘browning’ of white adipose tissue. Moreover, IL‐6, oncostatin M and SPARC are said to be implicated in cancer 27, 28. Of particular interest for this review, some of these myokines have been shown to induce an anti‐inflammatory response with each bout of exercise. During exercise, IL‐6 is the first detectable cytokine released from the contracting skeletal muscle cells into the blood. Muscle‐derived IL‐6 increases with exercise and contributes to a marked increase in circulating levels of IL‐6. A major difference between endotoxaemia and exercise‐induced production of cytokines is the absence of increased TNF‐α and IL‐1β in the latter state. However, a comparable increase in plasma IL‐6 concentrations is found in both conditions 29 (Fig. 1). Figure 1 Open in figure viewer PowerPoint During sepsis, there is a marked and rapid increase in circulating TNF and IL‐β, which is followed by an increase in IL‐6. In contrast, during exercise the marked increase in IL‐6 is not preceded by elevated TNF and IL‐β. Following acute exercise such as running at 75% of VO2max, the basal plasma IL‐6 may increase fivefold after 30 min 30, but the concentration may increase up to 100‐fold after a marathon 31. Of note, the exercise‐induced increase in plasma IL‐6 is not linear over time; repeated measurements during exercise show an accelerating increase in the IL‐6 in plasma in an almost exponential manner. Furthermore, the peak IL‐6 level is reached at the end of the exercise or shortly thereafter, followed by a rapid decrease towards pre‐exercise levels. The duration of exercise is the single most important factor that determines the magnitude of the systemic IL‐6 response. The longer the duration of the exercise, the more pronounced the systemic IL‐6 response will be. The IL‐6 response is also sensitive to the exercise intensity 32, which indirectly represents the muscle mass involved in the contractile activity. As contracting skeletal muscle per se is an important source of IL‐6 found in the plasma 33, 34, it is not surprising that exercise involving a limited muscle mass, for example the muscles of the upper extremities, may be insufficient to increase plasma IL‐6 above pre‐exercise level 35-37. In contrast, running – which involves several large muscle groups – is the mode of exercise where the most dramatic plasma IL‐6 increases have been observed. However, the exercise duration is the single most important factor determining the postexercise plasma IL‐6 amplitude. In fact, more than 50% of the variation in plasma IL‐6 following exercise can be explained by exercise duration alone 38. Another determining factor for the IL‐6 increase during exercise is the muscle glycogen content and hence training status of the muscle. Both intramuscular IL‐6 mRNA expression 39 and IL‐6 protein release 40 are markedly enhanced when intramuscular glycogen is low, indicating that muscular production of IL‐6 is related not only to exercise but also to glycogen content. Given that muscle glycogen level is less in untrained compared to trained individuals, this may explain why the IL‐6 response to the same relative intensity of exercise apparently decreases with training adaptation 38. It is worth noting that while plasma IL‐6 appears to be downregulated by training, the muscular expression of the IL‐6 receptor appears to be upregulated, suggesting that IL‐6 signalling may be enhanced in trained compared to untrained muscle 38. While low muscle glycogen exacerbates the IL‐6 response, a number of studies have demonstrated that glucose ingestion during exercise attenuates the exercise‐induced increase in plasma IL‐6 29, 41-50. Taken together, the systemic IL‐6 response to exercise is dependent on the duration and intensity of exercise, the muscle mass engaged during exercise, the muscular glycogen level and whether or not carbohydrate is ingested during the exercise, whereas the mode of exercise has little impact. As IL‐6 has been considered a classic pro‐inflammatory cytokine, it was first thought that the IL‐6 response was related to muscle damage. However, it soon became clear that eccentric exercise associated with muscle damage is not associated with a larger increase in plasma IL‐6 compared with exercise involving concentric ‘nondamaging’ muscle contractions, which clearly demonstrates that muscle damage is not required to increase plasma IL‐6 during exercise. Rather, eccentric exercise may result in a delayed peak and a slower decrease in plasma IL‐6 during recovery 29. In relation to acute exercise, IL‐6 induces a subsequent increase in the production of IL‐1 receptor antagonist (IL‐1ra) and IL‐10 by blood mononuclear cells, thus stimulating the occurrence of anti‐inflammatory cytokines 51. IL‐1ra inhibits IL‐1β signal transduction 52, and IL‐10 is capable of inhibiting synthesis of pro‐inflammatory cytokines such as TNF‐α 53. An experimental study confirmed that a bout of exercise induces significant anti‐inflammatory actions. In a model of ‘low‐grade inflammation’, a very low dose of E. coli endotoxin, which would induce a modest increase in plasma TNF‐α concentrations, was administered to healthy subjects, who were randomized to either rest or exercise prior to the endotoxin administration 54. Endotoxin induced a two‐ to threefold increase in circulating levels of TNF‐α. However, when participants performed 3 h of ergometer cycling, the TNF‐α response was totally blunted. The effects of exercise could be mimicked by an infusion of IL‐6 that suppressed the endotoxin‐induced TNF‐α production 54. This study was in agreement with studies showing that IL‐6 inhibits lipopolysaccharide (LPS)‐induced TNF‐α production in cultured human monocytes 55 and that levels of TNF‐α are elevated in anti‐IL‐6‐treated mice and in IL‐6‐deficient knockout mice 56. The data demonstrate that an acute bout of exercise induces a strong anti‐inflammatory effect that at least in part appears to be mediated by IL‐6, although other mediators may be involved. Thus, exercise induces high levels of epinephrine and infusion of epinephrine has been shown to blunt the appearance of TNF‐α in response to endotoxin in vivo in humans, suggesting that both IL‐6 and epinephrine contribute to the anti‐inflammatory effects elicited by an acute bout of exercise 57. Given that treatment with cortisol has been proven effective in patients with severe inflammatory disorders, it is interesting that exercise provokes a short‐term increase in cortisol. Of note, the exercise‐induced increase in cortisol appears to be mediated by IL‐6. Support for this proposal is based on a study in which IL‐6 was infused into normal healthy volunteers in concentrations to mimic the exercise effect on the plasma concentration of IL‐6. Interleukin‐6 induced increased levels of plasma cortisol and, consequently, an increase in circulating neutrophils and a decrease in the lymphocyte number without effects on either plasma epinephrine, body temperature, mean arterial pressure or heart rate 51. The link between exercise‐induced lymphocyte changes and an effect of IL‐6 on cortisol production is supported further by studies demonstrating that carbohydrate loading during exercise attenuates the exercise effect on IL‐6, lymphocyte number and cortisol 58, 45 and that antioxidant treatment blunts both the release of IL‐6 from contracting human muscle and the exercise‐induced increase in plasma cortisol levels 33 (Fig. 2). Figure 2 Open in figure viewer PowerPoint 11 Evidence suggests that contracting skeletal muscle leads to increased cytosolic Ca2 + and activation of p38 MAPK and/or calcineurin, which leads to activation of transcription factors depending upon these upstream events. IL‐6 has anti‐inflammatory effects as it inhibits TNF production, but stimulates the occurrence of the anti‐inflammatory cytokines IL‐1ra and IL‐10. Furthermore, IL‐6 stimulates cortisol production and hence neutrocytosis and lymphopenia. Adapted and further modified from ref.

Anti‐inflammatory effects of training adaptation Regular exercise training reduces basal IL‐6 production as well as the magnitude of the acute exercise IL‐6 response by counteracting several potential stimuli of IL‐6. Accordingly, a decreased plasma IL‐6 concentration at rest as well as in response to exercise appears to characterize normal training adaptation 38. Evidence exists for the detrimental effects of the accumulation of fat in the visceral cavity (i.e. visceral fat), in the liver and in skeletal muscle 59, which might exacerbate systemic inflammation and consequently activate a network of inflammatory pathways that promote the development of insulin resistance, atherosclerosis and neurodegeneration, as well as a network of chronic diseases, including CVD, T2DM, Alzheimer's disease and other disorders belonging to the ‘diseasome’ of physical inactivity 1. Abdominal adiposity has consistently been associated with CVD, T2DM, dementia, colon cancer and breast cancer as well as all‐cause mortality independently of body mass index 1. Thus, the health consequences of increased abdominal adiposity and physical inactivity are similar. Moreover, both physical inactivity 29 and abdominal adiposity 60 are associated with persistent systemic low‐grade inflammation, and a direct link between physical inactivity and visceral fat has been established in both rodents 61 and humans 62-65. We have shown that when daily stepping was reduced from 10,000 to 1,500 steps for 14 days, it resulted in a significant increase in intra‐abdominal fat mass without a change in total fat mass while total fat‐free mass and body mass index decreased 62. The finding that physical inactivity provokes accumulation of visceral fat has been supported in several studies 63, 65, 66. Chronic systemic inflammation predisposes to insulin resistance, dyslipidaemia, endothelial dysfunction, accelerated atherosclerosis, neurodegeneration, anaemia and muscle waste, which may contribute to disability and decreased physical activity. Lack of physical activity will, in turn, provoke accumulation of visceral fat and thereby further enhance inflammation and the onset of metabolic disorders, atherosclerosis and the development of a network of chronic diseases. A vicious circle of chronic inflammation can be established, in which the state of chronic inflammation is accompanied by anaemia, tiredness and muscle waste which together with other comorbidities and the disease‐specific symptoms will lead to further deconditioning and a worsening of the chronic inflammation, which again will negatively affect cardiovascular performance and physical activity in a positive feedback loop 11 (Fig. 3). Regular exercise protects against accumulation of abdominal fat 67 and thereby also against chronic systemic inflammation. Evidence exists that this effect may at least in part be mediated by myokines. Interleukin‐15 is robustly upregulated in trained human muscle 68 and appears to be involved in the long‐term regulation of abdominal obesity, as overexpression of IL‐15 protects mice from the accumulation of visceral fat. IL‐15 is an anabolic factor that is highly expressed in skeletal muscle 69; it induces an increase in the accumulation of the protein myosin heavy chain in differentiated muscle cells 70 and stimulates myogenic differentiation independently of insulin‐like growth factors 71. Despite anabolic effects on skeletal muscle in vitro and in vivo 72, IL‐15 is involved in reducing adipose tissue mass 73. Moreover, IL‐15 decreases lipid deposition in preadipocytes and decreases the mass of white adipose tissue 74, 75. And it has been hypothesized that IL‐15 may aid in decreasing or even inhibiting the negative effects of TNF‐α in patients where a low‐grade chronic inflammatory condition is present 76. Thus, IL‐15 seems to have a role in muscle–fat crosstalk (Fig. 3). Figure 3 Open in figure viewer PowerPoint 11 Chronic systemic inflammation predisposes to insulin resistance, dyslipidaemia, endothelial dysfunction, accelerated atherosclerosis, neurodegeneration, anaemia and muscle waste, which may contribute to disability and decreased physical activity. Lack of physical activity will provoke accumulation of visceral fat and thereby further enhance inflammation and the onset of metabolic disorders, atherosclerosis and the development of a network of chronic diseases. A vicious circle of chronic inflammation in inflammatory rheumatic diseases, in which the state of chronic inflammation is accompanied by anaemia, tiredness and muscle waste which together with other comorbidities and the disease‐specific symptoms will lead to further deconditioning and a worsening of the chronic inflammation, which again will negatively affect cardiovascular performance and physical activity in a positive feedback loop. Adapted and further modified from ref. Strong physiological evidence exists in humans that IL‐6 mediates both lipolysis and fat oxidation 77 – effects that are mediated via AMPK 78. Thus, both IL‐15 and IL‐6 play important roles in lipid metabolism. Moreover, brain‐derived neurotropic factor (BDNF) is also hypothesized to be a myokine that works in an autocrine or paracrine fashion with strong effects on peripheral metabolism, including fat oxidation and a subsequent effect on the size of adipose tissue 79. Furthermore, a large muscle mass might protect against accumulation of visceral fat, and several myokines including IL‐4, IL‐6, IL‐7, IL‐15, LIF and myostatin are involved in the regulation of skeletal muscle growth and maintenance 23.

Exercise, inflammation and type 2 diabetes Evidence exists that inflammation is involved in the development and/or progression of T2DM 2-5. Elevated circulating levels of acute‐phase proteins such as C‐reactive protein (CRP) as well as cytokines and chemokines are found in individuals with T2DM 80-85, and elevated levels of IL‐1β, IL‐6, IL‐1ra and CRP are predictive of T2DM 81, 86, 87. Strong evidence exists that IL‐1β is a key pro‐inflammatory mediator of β‐cell damage in T2DM 3, 88, 89. Thus, depletion of resident islet macrophages in high‐fat‐fed transgenic mice with islet amyloid formation may reduce IL‐1β expression, improve β‐cell insulin secretion and restore glucose tolerance 90. Moreover, inhibition of IL‐1β ameliorates β‐cell dysfunction and glucose homoeostasis in individuals with T2DM 91. IL‐1 antagonism has also been shown to lower chronic inflammation and cortisol levels 92, 93. In addition to the well‐documented detrimental effects of chronic activation of the IL‐1β system, recent findings from the Donath group demonstrate a possible physiological role for IL‐1β in glucose metabolism. They found that feeding induced a physiological increase in the number of peritoneal macrophages that secreted IL‐1β, in a glucose‐dependent manner, and that IL‐1β contributed to the postprandial stimulation of insulin secretion 94. While chronic elevation of IL‐1β has been proven to play a role in β‐cell damage, TNF‐α has been identified as a key molecule in peripheral insulin resistance. This evidence is based on classic studies in cultured cells 95 and in TNF‐α knockout mice 96. Further evidence was found when TNF‐α infusion was shown to inhibit whole‐body insulin‐mediated glucose uptake and signal transduction in healthy humans 97. The latter study showed that TNF‐α directly impairs peripheral insulin‐stimulated glucose uptake via an impaired phosphorylation of Akt substrate 160, the most proximal step identified in the canonical insulin signalling cascade regulating GLUT4 translocation and glucose uptake 97 We have contributed to identify a potential communication between insulin‐resistant human skeletal muscle and primary β‐cells involving TNF‐α, which suggests a mechanism by which insulin‐resistant muscle can cause impaired function of β‐cells 98. Human skeletal muscle cells were cultured with TNF‐α to induce insulin resistance. We found that human myotubes express and release a different panel of myokines depending on their insulin sensitivity, with each panel exerting differential effects on β‐cells. Conditioned medium from control myotubes increased proliferation and glucose‐stimulated insulin secretion from primary β‐cells, whereas conditioned medium from TNF‐α‐treated insulin‐resistant myotubes exerted detrimental effects that were either independent or dependent on the presence of TNF‐α. This study suggest a possible route of communication between skeletal muscle and β‐cells that is modulated by insulin resistance and could contribute to normal β‐cell functional mass in healthy subjects, as well as to the decrease seen in T2DM 98. As said, TNF‐α is a key molecule in insulin resistance. Therefore, exercise may at least partly enhance insulin sensitivity via an inhibition of TNF‐α. The finding that exercise provokes an increase in circulating IL‐1ra may contribute to protect against IL‐1‐mediated destruction of β‐cells. Correlational studies show that IL‐6 is strongly associated with chronic inflammatory states, including low‐grade inflammation associated with obesity and type 2 diabetes mellitus 99. In obesity, adipose tissue immune cells have emerged as the major source of elevated circulating IL‐6 levels 100. As a result of these findings, IL‐6 has long been recognized as an initiator of insulin resistance. However, a growing body of evidence identifies IL‐6 as a homoeostatic regulator of energy and glucose metabolism 101. The ‘dogma’ that IL‐6 induces insulin resistance has been challenged by the findings that IL‐6 is both produced 102, 103 and subsequently released 34, 40 from contracting skeletal muscle cells because physical exercise training is known to increase insulin sensitivity 104. Like leptin, IL‐6 has been shown to activate AMPK in both skeletal muscle and adipose tissue 105-108. Activation of AMPK may increase glucose uptake 109 via mechanisms thought to involve enhanced insulin signal transduction 107, 110. IL‐6 increased insulin‐stimulated glucose uptake in vitro, while infusion of recombinant human IL‐6 into healthy humans during a hyperinsulinaemic, euglycaemic clamp increased glucose infusion rate without affecting the total suppression of endogenous glucose production 107. The effects of IL‐6 on glucose uptake in vitro appeared to be mediated by activation of AMPK 107. Apart from the effects of IL‐6 on glucose metabolism, several studies have reported that IL‐6 can increase intramyocellular 107, 111, 112 or whole‐body 77 fatty acid oxidation. In support, mice lacking IL‐6 expression develop systemic insulin resistance and late‐onset obesity 113. IL‐6 also stimulates β‐cell proliferation, prevents apoptosis caused by metabolic stress and regulates β‐cell mass in vivo 114. Thus, it appears that exercise‐induced IL‐6 production may be directly involved in the expansion of pancreatic β‐cell mass that is needed for functional β‐cell compensation when an increased metabolic demand is present 114. Moreover, elevated IL‐6 concentrations in response to exercise stimulate glucagon‐like peptide‐1 secretion from intestinal L‐cells and pancreatic β‐cells, which improves insulin secretion 115, thus suggesting that IL‐6 is involved in an endocrine loop, implicating IL‐6 in a beneficial regulation of insulin secretion, which may contribute to protect against T2DM or progression of the disease. Interleukin‐6 is also a mediator of the glucose regulatory action of the insulinotropic peptide (GIP) 116. Evidence for a direct anti‐inflammatory effect of IL‐6 exists as IL‐6 acts as a Th2 cytokine in obesity 117. In addition, it has been shown that IL‐6 receptor signalling, both in hepatocytes and in macrophages, limits systemic inflammation thereby improving systemic glucose homoeostasis in lean and obese mice 118, 119. Acute administration of IL‐6 is associated with improved peripheral fuel availability and increased insulin sensitivity in the periphery 107. Moreover, recent evidence indicates that IL‐6 trans‐signalling is enhanced in the CNS of obese mice, allowing IL‐6 to exert its beneficial metabolic effects even under conditions of leptin resistance 101. Taking these findings into consideration, exercise‐induced elevation of IL‐6 might serve as an adaptive mechanism in an attempt to increase insulin production and improve glucose tolerance. Moreover, IL‐6 stimulates IL‐1ra, thereby inhibiting IL‐1 signalling and hence limiting pancreas damage. The finding that IL‐6 inhibits TNF production may contribute to stimulate peripheral insulin sensitivity.

Exercise, inflammation and CVD CVD is associated with chronic low‐level inflammation, including elevations in circulating pro‐inflammatory cytokines and the acute‐phase reactant CRP (C‐reactive protein) 120, 121. It is difficult to determine whether inflammation is a cause or a consequence of particular disorders, but evidence suggests it may play a key role in the pathogenesis of CVD and other chronic diseases 122-125. In vivo studies appear to support a beneficial role for IL‐6 as lack of IL‐6 has been shown to promote atherosclerosis in both C57BL/6 126 and apolipoprotein E (ApoE)‐deficient mice 127.In contrast, TNF‐α has been suggested to play a direct role in atherosclerosis 128, 129. TNF‐α is present in the arterial wall with atherosclerosis 130 and induces the expression of adhesion molecules such as intracellular adhesion molecule‐1 (ICAM‐1) 131 and E‐selectin 132. TNF‐α has also been shown to impair the lipid profile 23, 133 via increased hepatic free fatty acid (FFA) and triglyceride (TG) synthesis, and decreased endothelium lipoprotein lipase activity, thus potentially leading to increased TG levels, reduced high‐density lipoprotein (HDL) levels and increased synthesis of the highly atherogenic light‐density lipoprotein (LDL) particles 134. Finally, TNF‐α has been shown to upregulate endothelial cellular adhesion molecule expression and downregulate the expression of endothelial nitric oxide synthase and cyclooxygenase‐1, resulting in impaired endothelial‐dependent dilatation 135. Thus, evidence suggests that increased TNF‐α levels may predispose to endothelial dysfunction and subsequent atherosclerosis 136-138. Clinical evidence also exists that TNF‐α blockers may prevent progression of intima–media thickness and pulse wave velocity in patients with inflammatory arthritis 128, 139. Numerous clinical studies have linked elevated TNF‐α levels to a worsened prognosis in patients with heart failure 6, 140. Furthermore, animal studies have shown that administration or overexpression of TNF‐α leads to heart failure, and blockade of TNF‐α improves cardiac function in models of heart failure 141-143. Small‐scale studies using etanercept demonstrated a clinical benefit to TNF‐α blockade with improved left ventricular function 144, 145. However, large‐scale clinical studies in which TNF‐α has been targeted have shown negative effects 146. It has been speculated that the outcome of these studies was dependent on the dose. The patients receiving high‐dose TNF‐α blockade had a worsening of their prognosis, whereas the patients receiving the low doses had a trend towards a beneficial effect. It appears that the wrong therapeutic threshold may have been applied to TNF‐α blockade and that a modest lowering of TNF‐α levels using low‐dose pharmacological inhibition might have proven successful. Interestingly, this is exactly what could be achieved with exercise training.