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Originally published online as doi:10.1189/jlb.0505247 on July 20, 2005

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(Journal of Leukocyte Biology. 2005;78:819-835.)
© 2005 by Society for Leukocyte Biology

Physical activity and modulation of systemic low-level inflammation

Helle Bruunsgaard1

Centre of Inflammation and Metabolism, Department of Infectious Diseases, Copenhagen Muscle Research Centre, Rigshospitalet, University Hospital of Copenhagen, Faculty of Health Sciences, University of Copenhagen, Denmark

1Correspondence: Centre of Inflammation and Metabolism, Department of Infectious Diseases, Copenhagen Muscle Research Centre, Rigshospitalet, University Hospital of Copenhagen, Faculty of Health Sciences, University of Copenhagen, Rigshospitalet M7641, Blegdamsvej 9, DK-2100 Copenhagen East, Denmark. E-mail: infdishb{at}rh.dk


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ABSTRACT
 
It has been recognized for some time that cardiovascular disease and type 2 diabetes are, to a major extent, inflammatory disorders associated with an environment characterized by a sedentary lifestyle together with abundant intakes of calories. Systemic low-level inflammation is suggested to be a cause as well as consequence of pathological processes with local tumor necrosis factor {alpha} production as an important biological driver. It is hypothesized that physical inactivity contributes to an enhanced proinflammatory burden independently of obesity, as regular muscle contractions mediate signals with myokines/cytokines as important messengers, which suppress proinflammatory activity at distant sites as well as within skeletal muscle. Muscle-derived interleukin (IL)-6 is considered to possess a central role in anti-inflammatory activities and health beneficial effects in relation to physical exercise. It is discussed how this fits the consistent observation that enhanced plasma levels of IL-6 represent a strong risk marker in chronic disorders associated with systemic low-level inflammation and all-cause mortality.

Key Words: myokines • TNF-{alpha} • IL-6 • proinflammatory • anti-inflammatory • exercise


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INTRODUCTION
 
During the last decade, it has become clear that inflammatory mechanisms are key players in pathological processes of several chronic diseases such as ischemic cardiovascular disease (CVD) [1 ], colorectal cancer [2 ], stroke [3 ], type 2 diabetes (T2D) [4 ], chronic obstructive pulmonary disease (COPD) [5 ], and Alzheimer’s disease [6 ], which are among the most common causes of mortality in the Western world. At the same time, it has been recognized that pleiotropic cytokines are not only important signals in immune function, as they also represent important regulators of endocrine systems, the metabolism, the coagulation system, and the brain function [7 ]. In addition, it has been discovered recently that circulating levels of cytokines in vivo are affected significantly by contributions of cells outside the immune system such as adipose tissue, skeletal muscle, and endothelial cells in healthy humans; e.g., 30% of interleukin (IL)-6 in plasma is derived from fat tissue [8 ] (Fig. 1 ). The concept of regulatory adipokines has developed together with the discovery of fat tissue as an important endocrine organ, producing and secreting classical cytokines including tumor necrosis factor (TNF)-{alpha}, IL-6, IL-18, as well as a wide range of other new peptides [9 , 10 ]. Moreover, at the millennium, it was demonstrated that working skeletal muscles produce and also release cytokines to the circulation [7 ]. Considering that skeletal muscle is the largest organ in the body, the perspective of this finding is revolutionary, and it provides a molecular explanation about a molecular level by which we may understand how exercise mediates some of the health beneficial effects in relation to chronic disorders associated with systemic low-level inflammation.



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  		Figure 1. Sources of cytokines. A wide range of organs and different cell types contribute to the production of cytokines, which possess local as well as endocrine activities, and act as important regulators of the metabolism and immune functions.

The purpose of the present review is to discuss how physical exercise is able to modulate cytokine production. The hypothesis is discussed that muscle contractions reduce systemic low-level inflammation in several chronic diseases, as skeletal muscle acts as an endocrine organ, which is able to influence the metabolism and modify cytokine production in other tissues and organs through signals mediated by "myokines." Mainly, activities of TNF-{alpha} and IL-6 are reviewed as models of links amongst physical activity, the metabolism, endocrine systems, and the immune system. However, it would be naïve not to recognize that other cytokines are relevant in this context as well.


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SYSTEMIC LOW-LEVEL INFLAMMATION, LIFESTYLE FACTORS, AND CHRONIC INFLAMMATORY DISORDERS
 
New and more sensitive assays for proinflammatory products have demonstrated an increased risk of all-cause mortality among persons who were previously thought to have circulating (plasma/serum) values within the normal range. Systemic low-level inflammation is defined as two- to fourfold elevations in circulating levels of proinflammatory and anti-inflammatory cytokines, natural occurring cytokine antagonists, and acute-phase proteins, as well as minor increases in counts of neutrophils and natural killer cells [11 ]. Although these increases are far from levels observed during acute, severe infections, systemic low-level inflammation is strongly associated with increasing age, lifestyle factors such as smoking, obesity, and dietary patterns, together with increased risk of CVD, T2D, COPD, cognitive decline, and wasting/cachexia (loss of skeletal muscle cells) [4 , 12 13 14 15 16 17 18 19 20 21 ]. Moreover, systemic low-level inflammation is a strong, consistent, and independent predictor of all-cause mortality and CVD-cause mortality in elderly populations [22 23 24 25 26 27 28 29 30 31 32 ].

These observations lead to the speculation whether individual mediators in the cytokine network are causal related to specific pathology or if systemic low-level inflammation represents a spillover from pathological processes. It has been suggested that insufficient proinflammatory responses can lead to increased susceptibility to infections and cancer, whereas excessive responses cause morbidity and mortality in diseases such as atherosclerosis, diabetes, Alzheimer’s disease, autoimmune disease, and shock during acute infections [33 ]. Circulating levels of inflammatory mediators are often strongly correlated with each other as a result of their tight, regulated production (Fig. 2 ). Moreover, levels of inflammatory mediators are correlated with other risk factors in chronic morbidity, including levels of fibrinogen, albumin, cholesterol, arterial blood pressure, and body mass index (BMI), among others (Fig. 3 ). This considerable covariance makes it difficult to separate effects from each other and to make causal analyses in epidemiological designs and in some experimental studies. Nevertheless, in my opinion, TNF-{alpha} deserves attention as a key player in systemic low-level inflammation and associated chronic diseases, as it promotes a proathersclerotic, procoagualant, and procachectic profile.



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  		Figure 2. The acute-phase response and the cytokine response in exercise. Shaded arrows mark positive stimulation. Solid arrow marks inhibition. IL-1Ra, IL-1 receptor antagonist; sTNFRs, soluble TNF receptors; CNS, central nervous system.



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  		Figure 3. Inflammatory mediators interact with the metabolism and several endocrine systems. See text for further details.


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ACTIVITIES OF TNF-{alpha} IN CHRONIC, INFLAMMATORY DISEASE
 
TNF-{alpha} is an early mediator of local inflammatory processes as well as an initiator of the systemic acute-phase response (Fig. 2) . It has been demonstrated recently that acute infections such as respiratory tract infections and urinary tract infections are associated with a transient increase in the risk of vascular events including stroke and myocardial infarction [34 ], indicating a connection amongst infections, immune activity, and thromboembolic complications. Consistent with this, TNF-{alpha} increases independently of IL-6 systemic levels of plasminogen activator inhibitor 1, which is an inhibitor of fibrinolysis and a risk factor in the metabolic syndrome and CVD [35 ], and TNF-{alpha} stimulates via IL-6 the production of fibrinogen [36 ]. In addition, low-grade activation of the TNF system and systemic low-level inflammation are observed in relation to chronic, asymptomatic infections such as chlamydia pneumoniae [37 ], bacteriuria [38 ], and dental infections [39 ], which are risk factors in atherosclerosis, probably through their contribution to the systemic inflammatory burden [40 ]. However, TNF-{alpha} production is not restricted to the context of infections.

Obesity is strongly associated with enhanced circulating TNF-{alpha} levels, whereas weight loss reduces systemic levels [41 ]. Adipose tissue from obese individuals shows accumulation of macrophages, which provide the major cellular source of a concomitant, enhanced, local expression of the TNF-{alpha} protein [42 , 43 ]. TNF-{alpha} induces insulin resistance in experimental animal models [44 , 45 ] by mechanisms that involve serine phosphorylation of the insulin receptor substrate 1 (IRS-1) [46 , 47 ]. This phosphorylation reduces insulin receptor tyrosine kinase activity in response to insulin and the ability of IRS-1 to associate with the insulin receptor and thereby, is downstream signaling- and insulin action-inhibited (see refs. [48 , 49 ] for recent reviews). The responsible intracellular pathways involve activation of c-Jun N-terminal kinases [50 ] and the inhibitor of {kappa}B kinase (IKK) [51 , 52 ], whereas activation of members in the suppressor of cytokine signaling (SOCS) family represents alternative intracellular stress pathways in cytokine-mediated inhibition of insulin signaling [53 , 54 ]. In addition, TNF-{alpha} causes insulin resistance indirectly, as it induces lipolysis in adipocytes [55 , 56 ] with an increased release of free fatty acids (FFA), which has also been implicated as a causative factor in phosphorylation of IRS-1 [48 , 49 ]. Enhanced levels of FFA are accompanied by hypertriglyceridemia, low high-density lipoprotein (HDL) cholesterol, and elevated, small, dense low-density lipoprotein in the circulation (reviewed in refs. [49 , 57 ]). Finally, increased TNF-{alpha} production is associated with hypertension through activation of the renin-angiotensin system, but the precise interaction remains to be described [58 ]. Accordingly, TNF-{alpha} is a potential biological driver in the metabolic syndrome characterized by abdominal obesity, hypertension, a reduced level of HDL, elevated triglycerides, and high-fasting glucose [16 ] and constitutes an important risk factor in atherosclerosis and T2D (Fig. 4 ).



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  		Figure 4. TNF-{alpha} is a potential driver in the metabolic syndrome. Fat tissue produces TNF-{alpha}, and circulating levels of TNF-{alpha} are correlated with the fat mass. Muscle contractions inhibit TNF-{alpha} production in vivo, and physical inactivity is associated with high circulating levels of TNF-{alpha}. Hypertension may induce increased production of TNF-{alpha} and vice versa. TNF-{alpha} induces insulin resistance and dyslipidaemia. See text for further details.

Vascular inflammation is central in the pathology of atherosclerosis [59 ]. TNF-{alpha} is a likely contributor, as it stimulates the expression of adhesion molecules by endothelial cells [60 ], and it induces endothelial dysfunction [61 ]. This provides a likely mechanism by which smoking is a risk factor in atherosclerosis: Smoking causes endothelial dysfunction accompanied by increased plasma levels of TNF-{alpha}, inflammatory mediators downstream in the inflammatory cascade [62 ], and enhanced circulating levels of soluble intercellular adhesion molecules [13 ], indicating vascular inflammation with spillover to the circulation. TNF-{alpha}-mediated local inflammatory processes are also considered to be central in the relation between smoking and COPD [63 ].

End stages of CVD, COPD, cancer, human immunodeficiency virus infections, and rheumatoid arthritis are often associated with wasting [17 , 20 , 21 , 64 65 66 ]. TNF-{alpha} is again a possible, common basis, as TNF-{alpha} is also named cachectin, as it increases the basal energy expenditure, and it leads to the erosion of lean body mass and a pronounced impairment in muscle protein balance [21 , 67 , 68 ]. Consistent with this, systemic low-level inflammation is correlated inversely with muscle mass, muscle strength, and functional capacity in elderly populations [14 , 18 , 69 , 70 ]. Moreover, muscle protein synthesis rate is related inversely to levels of TNF-{alpha} protein in skeletal muscle in elderly, frail humans [71 ].

Finally, studies of TNF-{alpha} polymorphisms have demonstrated that enhanced promoter activity is associated with unstable angina [72 ], insulin resistance [73 74 75 76 ], and increased risk of coronary heart disease in patients with T2D [77 ], supporting the hypothesis of TNF-{alpha} as an important driver in the metabolic syndrome and an active parameter in the elevated risk of CVD, which is associated with T2D and hypertension.

TNF-{alpha} works mainly locally, and TNF-{alpha} has a short half-life [78 ]. As a result, I suggest that an elevated level of TNF-{alpha} protein is not always detected in the circulation, despite enhanced gene transcription during systemic low-level inflammation. Rather, local TNF-{alpha} may stimulate production of IL-6 and subsequent mediators in the inflammatory cascade. In my opinion, it is likely that systemic low-level increases in IL-6, IL-8, C reactive protein (CRP), IL-1Ra, sTNFRs, IL-10, and inflammatory cells, among others, reflect on-going TNF-{alpha} production. For instance, plasma levels of TNF-{alpha} and sTNFRs are strongly correlated but sTNFRs are more stable in the circulation, and it has been suggested that they act as long-term markers of TNF-{alpha} [79 , 80 ]. Although low-grade increases in circulating levels of IL-6 and CRP are, in particular, strong predictors of inflammatory morbidity, I postulate that they reflect, to a large extent, a response to local TNF-{alpha} activities rather than TNF-{alpha}-independent pathological processes. In support of this view, polymorphisms in the CRP gene are not a risk factor in arterial thrombosis [81 ], although polymorphisms affect levels of CRP protein in the blood [82 ]. However, it would be naïve to point to TNF-{alpha} as the agent solely responsible in inflammatory disorders. Harmful activities can indeed be isolated for most inflammatory mediators, and considering the strong interactions, their activities should probably be considered together as parallel pathways (pathological effects in relation to sustained low-grade elevations in IL-6 is discussed in a later section). Furthermore, it is possible that attention should, to a higher degree, be directed toward the balance between proinflammatory activities and counteracting responses, as a strong anti-inflammatory response has turned out to be important for the course of chronic, inflammatory diseases; e.g., a polymorphism in the IL-10 promoter is associated with enhanced transcription activity and decreased mortality from CVD [83 ].

Accordingly, cytokines serve as a model on a molecular level, by which we can explain some of the interconnection amongst markers of inflammation, coagulation/fibrinolysis, glucose metabolism, lipid metabolism, the renin-angiotensin system, the hypothalamic-pituitary axis, and others in chronic disease associated with systemic low-level inflammation (Fig. 3) . It is possible that chronic disease and aging result from the constant use of these interfacial responses, as the organism trades short-term benefit for long-term damage. Systemic low-level inflammation may, to some extent, represent a spillover from local proinflammatory processes, which second-affect the function in other organs and tissues, providing a self-enhancing cascade (Fig. 5 ). This leads me to the hypothesis that systemic low-grade inflammation is a cause as well as a consequence of pathological processes, and local TNF-{alpha} production is an important biological driver. Then the question arises whether this negative circle can be interrupted.



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  		Figure 5. Systemic low-level inflammation, age-related risk factors, and morbidity. Systemic low-level inflammation is probably a cause and a consequence of age-related morbidity and associated risk factors, providing a self-enhancing cascade (see text).


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PHYSICAL ACTIVITY AND SYSTEMIC LOW-LEVEL INFLAMMATION
 
Physical activity offers protection against CVD [84 , 85 ], T2D [86 ], colorectal cancer [87 ], breast cancer [88 ], age-related cognitive decline [89 90 91 ], and all-cause mortality [92 ]. Furthermore, physical training is effective in the treatment of coronary heart disease [93 ], chronic heart failure [94 ], T2D [95 ], and COPD [96 ].

A recent number of papers have documented that self-reported physical activity or physical performance is correlated inversely with systemic low-level inflammation [32 , 70 , 97 98 99 100 101 102 103 104 105 106 ], although the lack of an association has also been reported [107 ], especially when adjusting for other factors in multivariate analyses [108 , 109 ] (Table 1 ). Positive associations between inflammatory markers and physical activity do not necessarily reflect a direct causal relationship; e.g., inflammatory mediators could simply act as markers of the health status and/or disease states. Weight and smoking are other important cofactors. It is probable that different degrees of contributions from these factors explain inconsistencies between studies. However, a high self-reported degree of physical activity is associated with attenuated circulating levels of TNF-{alpha}, IL-6, CRP, and SAA compared with those devoted to a sedentary lifestyle, independently of gender, age, smoking habits, BMI, total cholesterol, blood glucose, and blood pressure in the Greek ATTICA study [97 ]. Additionally, a similar association is observed within a subgroup with the metabolic syndrome and within a subgroup without [98 ]. Thus, a high level of physical activity is apparently associated with reduced levels of peripheral inflammatory mediators in the range of 20–60% compared with a sedentary lifestyle.


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  		Table 1. Self-Reported Physical Activity and Physical Performance in Relation to Systemic Low-Level Inflammation in Epidemiological Studies

Several studies have reported that exercise intervention programs reduce systemic low-level inflammation in patients with coronary heart disease [110 ], claudicants [111 ], and chronic heart failure [112 113 114 115 ] and in healthy, young adults [116 ]. A failure of a positive effect has been reported in old nursing home patients [117 ] and in obese elderly [118 ]. Markers of systemic low-level inflammation were not reduced in patients with chronic heart failure in one study, although decreased inflammation was detected locally within skeletal muscle [119 ] (Table 2 ). Different modes of training interventions are obvious reasons for discrepancies, e.g., endurance training versus resistance training; differences in the intensity of exercise; and the time duration of the single bout of exercise, as well as the full intervention program. In addition, a large interpersonal variability in peripheral inflammatory markers together with a considerable coefficient of variability in high-sensitivity cytokine assays make power problems common. Finally, the effect of physical activity is likely differentiated in disorders associated with systemic low-level inflammation. It is probably easier to revert endothelial dysfunction, insulin resistance, and dyslipidaemia in CVD than cachexia in a terminal state. In this regard, it is possible that there is a threshold beyond which systemic low-level inflammation represents an irreversible state; e.g., among patients with chronic heart failure, exercise training reduces plasma levels of TNF-{alpha} significantly among survivors but not among nonsurvivors [114 ]. Furthermore, the degree of activity in the TNF system at baseline was correlated inversely with the muscle strength after 12 weeks of resistance training in frail, old nursing home residents with multi-morbidity [119 ]. Nevertheless, it is a bit surprising that so many rather small studies actually are able to detect a reduction in systemic low-level inflammation by simply modulating the level of physical activity. This makes me conclude that cross-sectional studies, adjusted for several confounders together with interventional studies, suggest the existence of an independent relation between the level of physical activity and the degree of systemic low-level inflammation.


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  		Table 2. Inflammatory Parameters Following Interventions in the Level of Physical Activity


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AN ACUTE BOUT OF EXERCISE AND SYSTEMIC CHANGES IN LEVELS OF INFLAMMATORY MEDIATORS
 
A large number of studies have demonstrated that in relation to an acute bout of exercise, plasma levels of IL-6 increase exponentially up to 100-fold, with a total decline in the post-exercise period (see ref. [7 ] for a review). The IL-6 response is followed by elevations in circulating levels of inflammatory markers downstream in the acute-phase response, including IL-1Ra, IL-10, sTNFRs, and CRP [121 122 123 ] (Fig. 2) . The size of the response depends on the intensity, duration, and the mode of the exercise [7 ].

An initial study suggested that increased systemic levels of inflammatory parameters were related to muscle damage, as increased IL-6 levels were first detected in eccentric exercise models in which a positive correlation was also demonstrated to considerable creatine kinase (CK) increases [124 ]. However, later studies have not confirmed an association between peak IL-6 and peak CK levels [122 , 123 , 125 ]. Moreover, the IL-6 response is also observed during concentric exercise without any signs of muscle damage [126 ]. It has been suggested in a review of this literature that the marked and immediate increase in plasma IL-6 in response to exercise is independent of muscle damage, whereas muscle damage per se is followed by repair mechanisms, including invasion of macrophages into the muscle leading to IL-6 production, which occurs later and is of smaller magnitude than the IL-6 production related to muscle contractions [7 ].

Thus, physical exercise is associated with a systemic cytokine response comparable with the levels observed during severe infections, except the important difference is that increases in TNF-{alpha} and IL-1ß are minute if present at all when concentric exercise without muscle damage is performed (Fig. 2) . This indicates that in nontraumatic exercise models, the cytokine cascade differs importantly from the classical acute-phase response studied in infectious systems.


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PHYSICAL ACTIVITY AND MYOKINES
 
Monocytes are major producers of IL-6 in relation to infections. Accordingly, investigators turned first toward these cells to find the cellular source of IL-6 during physical exercise. Nevertheless, IL-6 mRNA or protein is not increased in circulating monocytes during or following concentric exercise without muscle damage [127 ].

Skeletal muscle cell cultures express several cytokines such as TNF-{alpha}, IL-6, IL-8, IL-15, and IFN-{gamma} [128 129 130 ]. A large number of studies have demonstrated enhanced IL-6 mRNA and increased transcription rate of the IL-6 gene in muscle biopsies during exercise with a rapid decrease in the post-exercise period [121 , 126 , 131 , 132 ]. IL-6 mRNA is not increased as a result of a systemic effect: In rats subjected to electrically stimulated contractions of the one hind leg while the other leg rests, IL-6 mRNA is elevated only in the muscle from the exercising leg [133 ]. In young men who perform a one-leg knee extensor exercise, IL-6 production in working muscles can account for the increase in plasma IL-6 during exercise when arterial-femoral venous differences are measured over the exercising and the resting leg and adjusted for the blood flow [134 ]. Immunohistochemical studies of skeletal muscle have demonstrated that type 1 and type 2 muscle fibers show marked and homogenous staining of IL-6 protein following exercise with a different, predominant accumulation, depending on the mode, intensity, and duration of the performance [135 136 137 ].

In summary, there is strong evidence in support of the hypothesis that skeletal muscle is a major source of IL-6 during nontraumatic exercise, as transcription levels, mRNA levels, and protein levels increase largely within muscle fibers, and the IL-6 release from working muscles can largely account for systemic increases during physical activity. In addition, small amounts of IL-6 are produced from adipose tissue [138 ], the brain [139 ], and peritendon tissue [140 ].

Several studies have reported that carbohydrate ingestion attenuates elevations in plasma IL-6 during running and cycling [131 , 141 142 143 ], whereas low muscle glycogen concentration further enhances IL-6 mRNA and the transcription rate for IL-6 [126 , 132 , 144 ].

The IL-6 release from working muscles is preserved in healthy, 70-year-old men [145 ] and in patients with T2D [146 ] when a two-leg knee extensor exercise is performed without muscle damage. In contrast, IL-6 mRNA is decreased in elderly men who perform downhill running [147 ], and the increase in systemic IL-6 levels is modest in elderly men who perform eccentric leg exercise [148 ] compared with young controls. The latter two models involve a major component of muscle damage, suggesting an age-associated impairment in leukocyte activation related to repair mechanisms rather than a blunted, muscle cell-derived IL-6 response induced by muscle contractions.

TNF-{alpha} mRNA is detectable in resting muscles, and it is increased in the elderly [71 ], in obesity [120 ], and in patients with T2D [128 ]. When young, healthy men perform 180 min of a knee extensor exercise, TNF-{alpha} mRNA increases only slightly (approximately fourfold, P=0.08) during the first 30 min of exercise, and after this time, it does not increase any further, whereas IL-6 increases ~100-fold in the same model [146 , 149 ]. Consistent with this, there is no measurable increase in systemic levels, and there is not detectable TNF-{alpha} net release from the working legs [146 , 149 ].

IL-8 mRNA increases pronouncedly in skeletal muscles in response to exercise [150 , 151 ], and IL-8 protein is expressed within the cytoplasma of muscle fibers [150 ]. Systemic IL-8 levels increase only in relation to exhaustive exercise with an eccentric component [141 , 152 , 153 ] but not in relation to concentric exercise without muscle damage [150 , 151 ]. The latter studies suggest that muscle-derived IL-8 has important autocrine or paracrine effects, which are yet unknown but could involve angiogenesis [150 ].

IL-15 is highly expressed in skeletal muscles [154 ], and it is believed to affect muscle anabolism [155 ]. Systemic IL-15 levels [122 ] or IL-15 mRNA in skeletal muscle [151 ] do not seem to be enhanced in response to concentric exercise without muscle damage, whereas increased circulating levels have been reported following eccentric modes of exercise [156 ].

Adiponectin is an adipocytokine, which exerts insulin-sensitizing effects on the liver and skeletal muscle and inhibits TNF-{alpha} production and endothelial activation induced by TNF-{alpha}. It has recently been reported that mRNA and protein are also expressed in skeletal muscle in response to in vivo lipopolysaccharide (LPS) administration in mice and following in vitro incubation with TNF-{alpha} and IFN-{gamma} in combination, but not IL-6 or IL-1ß in human myotubes [157 ].

Accordingly, skeletal muscles produce a wide range of different myokines/cytokines in vitro and in vivo. There is only evidence so far that IL-6 is released to the circulation during physical activity in models without muscle damage. It is, however, expected that new myokines will be identified with the increasing interests in physical activity and skeletal muscles in health and disease.


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IL-6 AND THE METABOLISM DURING EXERCISE
 
During exercise, skeletal muscles need to increase the uptake of glucose and FFA to generate adenosine 5'-triphosphate (ATP) and to quickly refill glycogen pools. Several metabolic genes are transcriptionally activated in the recovery phase from exercise, presumably with the purpose to rebuild energy stores [158 ]. If IL-6 is an energy sensor in the muscle, and IL-6 is released when the local glycogen content is low, it is possible that the large amounts of muscle-derived IL-6 in the circulation act as a hormone with the purpose to mobilize extracellular substrates and/or to augment substrate delivery during exercise [159 ].

IL-6 induces lipolysis and increased fat oxidation without causing triacylglycerolemia when it is administrated in doses mimicking systemic levels during exercise [160 , 161 ] as well as higher doses [162 ]. Consistent with this, IL-6 induces lipolysis in 3T3-LI adipocytes and increases fat oxidation in myotubes [160 ] and in isolated rat soleus muscle [163 ]. In addition, it has been suggested that IL-6 influences glucose homeostasis during exercise [164 ]. In the latter study, young men performed a bicycle exercise at three separate occasions, at a relative high intensity or at a low intensity, with or without an infusion of recombinant (r)IL-6, which matched the circulating concentration of IL-6 in the high-intensity trial. It was demonstrated by the use of stable isotopes that the endogenous glucose production, whole-body glucose disposal, and the metabolic clearance rate of glucose were higher during the rIL-6 infusion + low-intensity exercise than low-intensity exercise alone, despite identical exercise intensities and the same levels of insulin, glucagon, epinephrine, norepinephrine, cortisol, and growth hormone [165 ]. This finding implicates an entirely novel understanding of the role for IL-6 in glucose production and clearance.

Adenosine monophosphate-activated protein kinase (AMPK) is a fuel-sensing enzyme, which is activated by changes in the energy state of a cell, as well as by exposure to such hormones as adiponectin, leptin, and catecholamines [166 ]. Once activated, AMPK stimulates a variety of processes, which increase ATP generation, including fatty acid oxidation, glucose transport in cardiac and skeletal muscle, and glycolysis in heart and WBC. AMPK is activated in skeletal muscle during contractions, and it is thought to contribute to many of the changes in muscle fuel metabolism in relation to physical activity. IL-6 can activate AMPK in muscle and adipose tissue, and this contributes to the increase in AMPK activity in these tissues in response to exercise [167 ].

Infusion of rIL-6 exerts a positive feedback on IL-6 mRNA expression in skeletal muscle and in fat tissue in human volunteers when it is administrated in doses corresponding to levels observed during exercise [168 ]. Similar effects are observed in cell cultures of adipocytes [169 ] and liver cells [170 ], whereas a negative autoregulation is observed in monocytes [170 ]. IL-6 binds to the IL-6sR and the complex associates with two gp130 molecules for the initiation of intracellular signaling [171 ]. The gp130 receptor is expressed ubiquitously, whereas the IL-6R expression is restricted [172 ]. It has been demonstrated recently that muscle contraction induces post-exercise expression of IL-6R mRNA and protein in human skeletal muscle in vivo with the possible purpose to sensitize the muscle to the decreasing systemic IL-6 levels [173 ].

The exercise-induced expression of IL-6 mRNA in fat tissue is most pronounced in the recovery period, but it does not show the same relative increase as observed in skeletal muscle during physical activity, and the response is blunted by carbohydrate ingestion [138 ]. It is likely that muscle-derived IL-6 induces IL-6 production by adipose tissue, considering that the enhanced IL-6 production in adipose tissue is concomitant with an augmented need of FFA, as metabolism goes toward fat oxidation when glycogen stores are low [138 ]. Epinephrine infusion also induces a rapid, marked, but brief increase in IL-6 mRNA in subcutaneous adipose tissue of lean, healthy men with a concomitant increase in plasma IL-6, but this does not explain the prolonged expression of IL-6 mRNA following exercise [174 ].

Accordingly, there is evidence in support of the hypothesis that during physical exercise, IL-6 has the capacity to act in a "hormone-like" manner to direct the metabolism toward enhanced energy supply to working skeletal muscles, exerting especially strong effects on adipose tissue.


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PHYSICAL ACTIVITY AND MODULATION OF PROINFLAMMATORY ACTIVITY
 
Considering that nontraumatic muscle contractions induce a systemic cytokine response independently of TNF-{alpha} and IL-1ß (Fig. 2) , together with the health beneficial effect of physical activity in chronic inflammatory disorders in which local TNF-{alpha} and/or IL-1ß activities may act as initiators of pathological processes, it has recently been speculated whether regular exercise directly reduces the inflammatory burden by anti-inflammatory mechanisms [175 ].

IL-1Ra is a selective IL-1 antagonist, whereas IL-10 is a strong, anti-inflammatory cytokine, as it attenuates the cell-surface expression of TNFRs, and it inhibits the production of cytokines by monocytes and type 1 T cells (reviewed in ref. [176 ]). IL-10 and IL-1Ra arise in the circulation subsequently to IL-6 in relation to exercise [121 122 123 ]. In addition, cortisol levels and neutrophil counts are enhanced following exercise [177 , 178 ]. Neutrophils also exert, beside their antimicrobial properties, anti-inflammatory effects such as the production of sTNFRs, which bind circulating TNF-{alpha} [176 ]. It has previously been reviewed that although IL-6 is often classified as a proinflammatory cytokine, it also has many anti-inflammatory and immunosuppressive effects, as it stimulates the pituitary-adrenal axis, inhibits the synthesis of TNF-{alpha}, stimulates the production of IL-10 and IL-1Ra, and induces the shedding of TNFRs by neutrophils [179 ]. In accordance with this, the anti-inflammatory response, including elevated levels of IL-10, IL-1Ra, sTNFRs, and activation of the pituitary-adrenal axis, could likely be elicited by muscle-derived, systemic IL-6 during exercise, as rIL-6 infusions in similar doses also induce enhanced, systemic levels of these parameters, whereas levels of adrenaline and noradrenaline are not affected [180 ]. In addition, it is likely that other mediators also contribute to anti-inflammatory effects during exercise; e.g., adrenaline attenuates TNF-{alpha} production and enhances IL-10 production following LPS stimulation [181 ]. However, adrenaline only induces small increases in circulating levels of IL-6, which cannot account for the systemic IL-6 response observed during exercise [182 ].

With the aim to test the hypothesis that exercise-induced, anti-inflammatory activities have the potential to inhibit low-grade elevations in systemic TNF-{alpha}, Starkie et al. [183 ] performed three experiments in which healthy young men rested for 3 h (control), rode a bicycle for 3 h, and were infused with rIL-6 for 3 h. After 21/2 h, subjects received a bolus of Escherichia coli endotoxin in all experiments. This resulted in a twofold increase in circulating TNF-{alpha} in the control experiment, whereas the response was totally attenuated in relation to exercise or rIL-6 administration. This experiment supports the hypothesis that physical activity mediates strong anti-inflammatory effects by mechanisms that involve IL-6. Consistently, the TNF response was blunted in rats exercised before LPS administration, and the TNF response remained attenuated when LPS was administered up to 6 h after completion of exercise [184 ]. TNF-{alpha} overexpression returned to normal levels in TNFR knockout (KO) mice after only 1 h of exercise [185 ]. A modest decrease in TNF-{alpha} was also observed in IL-6 KO mice, suggesting the existence of anti-inflammatory exercise effects mediated via IL-6 and an IL-6-independent mechanism [185 ].

In accordance with experimental observations, TNF-{alpha} mRNA was increased in frail, old humans compared with young controls, but this overexpression declined after the performance of a training program for only 12 weeks [71 ]. Similarly, TNF-{alpha} mRNA in skeletal muscle declined in relation to a training intervention in patients with chronic heart failure, whereas a decline in systemic low-level inflammation was not detected [113 ]. However, TNF-{alpha} mRNA was not reduced in skeletal muscle after 8 weeks of bicycle exercise in obese adults [120 ].

In summary, there is good evidence that physical activity mediates anti-inflammatory effects in skeletal muscle and fat tissue. The underlying mechanisms appear to involve IL-6-dependent and -independent pathways. Even moderate physical activity is probably sufficient to induce the anti-inflammatory effects of exercise, as an increased transcription rate of the IL-6 gene is already detected after 30 min of two-leg extensor exercise at 60% of the individual maximal power output [132 ]. A two-legged knee extensor exercise at 50% of the maximal power output induces a 20-fold increase in plasma IL-6 but only a moderate increase in heart rate (113–122 beats/min), which is equivalent to a brisk walk [137 ]. When the same model is applied to elderly people, the IL-6 response is even more pronounced [145 ]. Thus, only 30 min of moderate exercise on a regular basis probably has the power to facilitate an anti-inflammatory environment characterized by enhanced levels of IL-10, IL-1Ra, and sTNFRs between bouts of physical activity. In theory, a reduced, local TNF-{alpha} production could explain a part of the decline in systemic low-level inflammation together with the improvement in symptoms and risk factors associated with the metabolic syndrome, CVD, T2D, and COPD in relation to regular exercise. In support of this, health beneficial effects of physical exercise have been ascribed to enhanced insulin sensitivity [186 ], an improved lipid profile [187 ], and decreased arterial blood pressure [188 ], representing factors that are all modulated by TNF-{alpha} as already discussed. Diet seems, however, to be more effective than physical activity in severe obesity.


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THE PARADOX OF IL-6 IN PHYSICAL ACTIVITY AND SYSTEMIC LOW-LEVEL INFLAMMATION
 
Considering that low-grade increases in circulating IL-6 constitute a strong prognostic risk factor in T2D, CVD, cognitive decline, functional disability, and all-cause mortality, it seems to represent a paradox that large amounts of IL-6 are released during an acute bout of exercise, which is, in general, considered to be health beneficial.

IL-6 is often postulated to cause insulin resistance, but at the same time, insulin sensitivity is increased during and following exercise when IL-6 is elevated pronouncedly in the circulation. Data in relation to IL-6 and insulin sensitivity are highly controversial (see ref. [189 ] for a recent review). In humans, neither splanchnic glucose output measured by the arterial-venous balance across the hepatosplanchnic tissue [190 ] nor isotopic tracer-determined endogenous glucose production is increased by human rIL-6 administration in physiological doses in healthy men [191 ] or in patients with T2D [160 ]. IL-6 KO mice develop late-onset obesity and glucose intolerance, which is reversed by IL-6 administration [192 ]. Consistent with this, mice with IL-6-secreting tumors reduce their fat mass and have low blood glucose levels, whereas the lean body mass is preserved [193 , 194 ]. Conversely, transgenic mice expressing constitutively active IKK-ß in hepatocytes have low-level activation of nuclear factor-{kappa}B and increased expression of IL-6 protein, but not TNF-{alpha}, in liver tissue, concomitant with insulin resistance in liver and systemically, which is improved by neutralizing IL-6 antibodies [195 ]. It is most consistent that IL-6 has been shown to suppress insulin sensitivity in the mouse liver [195 196 197 198 199 200 201 ], probably with the involvement of SOCS-3 as a mediator. With regard to adipose cells, it has been demonstrated that acute IL-6 treatment increases basal and insulin-stimulated glucose uptake in 3T3-LI adipocytes with an additive effect of insulin [202 ], but it has also been reported that IL-6 suppresses insulin-stimulated glucose transport in the same cell line [203 ]. Although skeletal muscle contributes to >90% of the glucose disposal in the body, only a few studies have investigated the relation between IL-6 and insulin sensitivity in this tissue in details. IL-6 enhances glycogen synthesis in skeletal muscle in the presence of insulin by a mechanism that involves increased Ser-473 phosphorylation of Act [204 ]. Conversely, it has been reported that acute IL-6 treatment in supraphysiological doses reduces insulin-stimulated glucose uptake in skeletal muscle, and this is associated with defects in insulin-stimulated IRS-1-associated phosphatidylinositol-3 kinase activity and increases in fatty acyl-coenzyme A levels during hyperinsulinemic-euglycemic clamps in mice [196 ]. Reverse effects of IL-6 in liver and skeletal muscle [197 , 204 ] may explain a part of the controversies. However, based on the present review, the role of IL-6 in insulin sensitivity appears to be inconclusive with contrasting findings in studies of mice versus humans, acute versus chronic elevations in IL-6 levels, and reverse effects in different tissues. In contrast, there is convincing evidence that IL-6 is a strong lipolytic factor, and considering that IL-6 also increases fat oxidation [161 ], it is unlikely that IL-6 causes serious dyslipidaemia.

IL-6 production is mainly regulated on the transcriptional level [205 ]. The IL-6 –174G/C promoter polymorphism is common [206 ]. The –174C variant is associated with low promoter activity in LPS or IL-1-stimulated HeLA cells and decreased plasma levels of IL-6 in healthy subjects aged 40–75 years [207 ]. The C variant is a risk factor in CVD [208 209 210 211 ], T2D [73 ], colorectal cancer [2 ], and all-cause mortality in old populations [210 , 212 ]. In accord, the C variant is associated with risk factors such as endothelial dysfunction [213 ], a high systolic blood pressure [208 ], elevated levels of fibrinogen [214 ], and high WBC counts [215 ]. The clinical effect interacts, moreover, with lifestyle factors such as smoking [210 ] and physical fitness [215 ]. Considering the experimental investigations of promoter activity [207 ], the association amongst the C variant, CVD, T2D, and colorectal cancer points toward a protective role of IL-6 in these disorders. However, the interpretation in the literature has widely been the opposite, as the C variant is associated with high plasma levels of IL-6 in several cohorts of elderly adults [210 , 214 , 216 ] and in patients with small abdominal aortic aneurisms [209 ], and moreover, the C variant is associated with increased levels of CRP [208 , 214 , 217 ]. Nonetheless, the opposite relation amongst plasma IL-6 and the –174C variant [207 , 218 , 219 ], no association [220 , 221 ], or an association in newborns but not in adults [222 ] has also been reported. It is likely that associations amongst cytokine polymorphisms, low-level inflammation, and morbidity are blurred by the accumulation of a wide range of other contributing factors in elderly populations and patients. Moreover, high plasma levels of IL-6 probably have a poor correlation with the capacity of IL-6 production in populations characterized by systemic low-level inflammation. A weak counteracting IL-6 response to local TNF-{alpha} activities could result in higher chronic circulating IL-6 levels as a result of an increased inflammatory burden, contrasting the intuitive thought of a direct association between low promoter activity and low plasma levels. In support of this hypothesis, low-grade increases in systemic IL-6 and the –174C polymorphism (low IL-6 transcription) were independent of each other, strongly associated with high mortality risk in nonsmoking octogenarians [210 ] (Fig. 6 ). Accordingly, polymorphism studies support that IL-6 plays an active part in disorders associated with systemic low-level inflammation, but the understanding of the effect is highly controversial in the literature. In my opinion, polymorphism studies indicate a protective role of IL-6 in CVD, T2D, and colorectal cancer based on the present review and discussion.



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  		Figure 6. The IL6 –174G>C promoter polymorphism and mortality in 234 nonsmoking 80-year-olds. Follow-up time is 5–6 years. HR, Hazard ratio; GG is reference for the C allele; IL-6, serum levels (continuous variable; from ref. [210 ]).

IL-6 has been implicated in anemia in chronic disease [223 ]. Studies in human liver cell cultures, mice, and human volunteers indicate that IL-6 induces the iron regulatory peptide hormone hepcidin during inflammation, and the IL-6-hepcidin axis is responsible for the hypoferremia of inflammation [224 ]. Furthermore, IL-6 has been implicated in anorexia and increased energy expenditure [162 , 192 , 193 ]. To my knowledge, these activities have only been evaluated in models with high circulating levels of IL-6, whereas the impact has not been explored in experimental models of systemic low-level inflammation.

IL-6 production appears on a turning point between dominance of proinflammatory and anti-inflammatory activity in the classical acute-phase response (Fig. 2) . Assuming that IL-6 mainly reflects local proinflammatory activities in the context of systemic low-level inflammation, it remains to be determined if IL-6 per se is counteracting the effect of TNF and/or IL-1ß. Considering that IL-6 induces an anti-inflammatory response and suppresses the production of TNF-{alpha}, it is possible that a critical balance between TNF-{alpha} and IL-6 is important in chronic, inflammatory morbidity. Consistent with this hypothesis, the TNF-308A promoter polymorphism (high TNF-{alpha} transcription) in combination with IL-6 –174C (low IL-6 transcription) is a risk factor in the development of T2D [73 ]. When IL-6 is produced independently of TNF-{alpha}/IL-1ß during physical activity, I suggest it exerts mainly anti-inflammatory activities. In addition, it is possible that large, short-lasting elevations in systemic IL-6 promote health beneficial activities contrasting chronic, low-grade increases, which promote procoagulant changes [225 , 226 ], the development of lymphoma [227 , 228 ], and perhaps insulin resistance [195 ]. This suggests that IL-6 may act as a double-edged sword in health and disease.


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CONCLUSION
 
It has been argued in the present review that systemic low-level inflammation is a cause and consequence of local pathological processes in chronic disorders with local TNF-{alpha} production as an important biological driver, as TNF-{alpha} promotes a proinflammatory, proatherosclerotic, a procoagulant, and a cachectic profile. I have suggested that subsequent mediators in the inflammatory cascade (IL-6, CRP, and others) are enhanced in systemic low-level inflammation as a response to local TNF-{alpha} production rather than independently of TNF-{alpha}.

Muscle contractions without trauma induce a myokine response, which is characterized by a large release of IL-6 from working muscles, independently of TNF-{alpha} and IL-1ß. It has been suggested that the contraction-induced IL-6 expression in skeletal muscle is a specific biochemical phenomenon with the purpose to mobilize substrate from fuel depots within the body to facilitate energy metabolism [159 ]. The IL-6 response is followed by a systemic anti-inflammatory response. This could provide a common underlying pathway by which TNF-{alpha} activity is attenuated after a single bout of exercise following rIL-6 administration and in response to training interventions, as discussed in this review. An exercise-induced reduction in the proinflammatory burden is a plausible way to explain a part of the relation amongst regular physical activity, prevention, and improved symptoms in chronic disorders associated with systemic low-level inflammation (Fig. 7) .



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  		Figure 7. The inflammatory burden in elderly populations. A wide range of factors contributes to systemic low-level inflammation in epidemiological studies. Physical activity is a counteracting factor.

It represents a new paradigm that skeletal muscle acts as an endocrine organ, which by contractions, stimulates the production and release of myokines, which can influence the metabolism and modify cytokine production in other tissues and organs. Based on the present review, I suggest a fine balance between proinflammatory and anti-inflammatory activity across different tissues and organs to keep the body optimally tuned. It has been recognized for the last decade that obesity disturbs such a balance by enhanced proinflammatory activities. Obviously, physical inactivity contributes indirectly to a proinflammatory burden through the tight relation to obesity. In addition, I speculate that physical inactivity causes a proinflammatory profile independently of obesity, as regular muscle contractions mediate signals with myokines as messengers that suppress proinflammatory activities at distant sites as well as within skeletal muscle. It has been suggested that high proinflammatory activity protects us against infections, but the price may be increased risk of chronic, inflammatory disorders such as CVD [83 ]. This risk is probably accentuated when it is combined with a lifestyle that evolves physical inactivity, smoking, and obesity.

We have probably only seen the top of the iceberg in the understanding of inflammatory processes in relation to physical activity, as new cytokines/myokines/adipokines are discovered all the time. In the future, it will be a major challenge to investigate pathways and to determine the interaction and regulatory role for the presently known myokines as well as the new myokines, which we will likely discover in the future. We also need to identify tissue-specific biomarkers of inflammation in the circulation. We need to discuss whom we will recommend to perform physical exercise in the future and how this activity should be carried out to optimize the myokine response. This will take large studies, which should address the necessary duration of the training program, intensities of the exercise, how many and which muscle groups should be involved, and if long-term indurance training is more effective with regard to anti-inflammatory activities than short-term, high-intensity resistance training. So far, physical activity appears to be an effective way to modulate proinflammatory activity in relation to disorders associated with atherosclerosis. This is likely a result of a reversal of endothelial dysfunction/activation, increased insulin sensitivity, a reduced arterial blood pressure, an improved lipid profile, and weight loss. We need to explore if there is a point when systemic low-level inflammation becomes irreversible; e.g., sarcopenia is to a major extent caused by physical inactivity, but we do not know if cachexia is reversible by physical exercise in chronic, inflammatory disorders. We also need to look for biomarkers to determine when we should motivate frail patients to exercise and when we should limit our efforts.

In conclusion, physiological experiments, molecular analyses, and epidemiological studies suggest together that physical activity per se mediates strong anti-inflammatory mechanisms with sufficient power to reduce proinflammatory activity in vitro and in vivo.


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ACKNOWLEDGEMENTS
 
Financial support was received from the Danish Medical Research Council (22-02-0261), the Danish National Research Foundation (Center of Inflammation and Metabolism 02-512-55), and The A. P. Møller Foundation for the Advancement of Medical Science. Professor Bente Klarlund Pedersen is acknowledged for inspiring discussions.

Received May 9, 2005; revised June 17, 2005; accepted June 19, 2005.


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REFERENCES
 
    1
  1. Hansson, G. K. (2005) Inflammation, atherosclerosis, and coronary artery disease N. Engl. J. Med. 352,1685-1695[Free Full Text]
    2. 2
  2. Landi, S., Moreno, V., Gioia-Patricola, L., Guino, E., Navarro, M., de Oca, J., Capella, G., Canzian, F. (2003) Association of common polymorphisms in inflammatory genes interleukin (IL)6, IL8, tumor necrosis factor {alpha}, NFKB1, and peroxisome proliferator-activated receptor {gamma} with colorectal cancer Cancer Res. 63,3560-3566[Abstract/Free Full Text]
    3. 3
  3. Hallenbeck, J. M. (2002) The many faces of tumor necrosis factor in stroke Nat. Med. 8,1363-1368[CrossRef][Medline]
    4. 4
  4. Pradhan, A. D., Manson, J. E., Rifai, N., Buring, J. E., Ridker, P. M. (2001) C-reactive protein, interleukin 6, and risk of developing type 2 diabetes mellitus JAMA 286,327-334[Abstract/Free Full Text]
    5. 5
  5. Gan, W. Q., Man, S. F., Senthilselvan, A., Sin, D. D. (2004) Association between chronic obstructive pulmonary disease and systemic inflammation: a systematic review and a meta-analysis Thorax 59,574-580[Abstract/Free Full Text]
    6. 6
  6. Akiyama, H., Barger, S., Barnum, S., Bradt, B., Bauer, J., Cole, G. M., Cooper, N. R., Eikelenboom, P., Emmerling, M., Fiebich, B. L., Finch, C. E., Frautschy, S., Griffin, W. S., Hampel, H., Hull, M., Landreth, G., Lue, L., Mrak, R., Mackenzie, I. R., McGeer, P. L., O’Banion, M. K., Pachter, J., Pasinetti, G., Plata-Salaman, C., Rogers, J., Rydel, R., Shen, Y., Streit, W., Strohmeyer, R., Tooyoma, I., Van Muiswinkel, F. L., Veerhuis, R., Walker, D., Webster, S., Wegrzyniak, B., Wenk, G., Wyss-Coray, T. (2000) Inflammation and Alzheimer’s disease Neurobiol. Aging 21,383-421[CrossRef][Medline]
    7. 7
  7. Febbraio, M. A., Pedersen, B. K. (2002) Muscle-derived interleukin-6: mechanisms for activation and possible biological roles FASEB J. 16,1335-1347[Abstract/Free Full Text]
    8. 8
  8. Mohamed-Ali, V., Goodrick, S., Rawesh, A., Katz, D. R., Miles, J. M., Yudkin, J. S., Klein, S., Coppack, S. W. (1997) Subcutaneous adipose tissue releases interleukin-6, but not tumor necrosis factor-{alpha}, in vivo J. Clin. Endocrinol. Metab. 82,4196-4200[Abstract/Free Full Text]
    9. 9
  9. Kershaw, E. E., Flier, J. S. (2004) Adipose tissue as an endocrine organ J. Clin. Endocrinol. Metab. 89,2548-2556[Abstract/Free Full Text]
    10. 10
  10. Guerre-Millo, M. (2004) Adipose tissue and adipokines: for better or worse Diabetes Metab. 30,13-19[Medline]
    11. 11
  11. Bruunsgaard, H., Pedersen, B. K. (2003) Age-related inflammatory cytokines and disease Immunol. Allergy Clin. North Am. 23,15-39[CrossRef][Medline]
    12. 12
  12. Bruunsgaard, H., Andersen-Ranberg, K., Jeune, B., Pedersen, A. N., Skinhoj, P., Pedersen, B. K. (1999) A high plasma concentration of TNF-{alpha} is associated with dementia in centenarians J. Gerontol. A Biol. Sci. Med. Sci. 54,M357-M364
    13. 13
  13. Bermudez, E. A., Rifai, N., Buring, J. E., Manson, J. E., Ridker, P. M. (2002) Relation between markers of systemic vascular inflammation and smoking in women Am. J. Cardiol. 89,1117-1119[CrossRef][Medline]
    14. 14
  14. Pedersen, M., Bruunsgaard, H., Weis, N., Hendel, H. W., Andreassen, B. U., Eldrup, E., Dela, F., Pedersen, B. K. (2003) Circulating levels of TNF-{alpha} and IL-6 - Relation to truncal fat mass and muscle mass in healthy elderly individuals and patients with type 2 diabetes Mech. Ageing Dev. 124,495-502[CrossRef][Medline]
    15. 15
  15. Esposito, K., Marfella, R., Ciotola, M., Di Palo, C., Giugliano, F., Giugliano, G., D’Armiento, M., D’Andrea, F., Giugliano, D. (2004) Effect of a Mediterranean-style diet on endothelial dysfunction and markers of vascular inflammation in the metabolic syndrome: a randomized trial JAMA 292,1440-1446[Abstract/Free Full Text]
    16. 16
  16. Willerson, J. T., Ridker, P. M. (2004) Inflammation as a cardiovascular risk factor Circulation 109,II2-10
    17. 17
  17. Di Francia, M., Barbier, D., Mege, J. L., Orehek, J. (1994) Tumor necrosis factor-{alpha} levels and weight loss in chronic obstructive pulmonary disease Am. J. Respir. Crit. Care Med. 150,1453-1455[Abstract]
    18. 18
  18. Ferrucci, L., Penninx, B. W., Volpato, S., Harris, T. B., Bandeen-Roche, K., Balfour, J., Leveille, S. G., Fried, L. P., Md, J. M. (2002) Change in muscle strength explains accelerated decline of physical function in older women with high interleukin-6 serum levels J. Am. Geriatr. Soc. 50,1947-1954[CrossRef][Medline]
    19. 19
  19. Yaffe, K., Lindquist, K., Penninx, B. W., Simonsick, E. M., Pahor, M., Kritchevsky, S., Launer, L., Kuller, L., Rubin, S., Harris, T. (2003) Inflammatory markers and cognition in well-functioning African-American and White elders Neurology 61,76-80[Abstract/Free Full Text]
    20. 20
  20. Roubenoff, R., Roubenoff, R. A., Cannon, J. G., Kehayias, J. J., Zhuang, H., Dawson-Hughes, B., Dinarello, C. A., Rosenberg, I. H. (1994) Rheumatoid cachexia: cytokine-driven hypermetabolism accompanying reduced body cell mass in chronic inflammation J. Clin. Invest. 93,2379-2386
    21. 21
  21. Tisdale, M. J. (1999) Wasting in cancer J. Nutr. 129,243S-246S[Abstract/Free Full Text]
    22. 22
  22. Harris, T. B., Ferrucci, L., Tracy, R. P., Corti, M. C., Wacholder, S., Ettinger, W. H. J., Heimovitz, H., Cohen, H. J., Wallace, R. (1999) Associations of elevated interleukin-6 and C-reactive protein levels with mortality in the elderly Am. J. Med. 106,506-512[CrossRef][Medline]
    23. 23
  23. Volpato, S., Guralnik, J. M., Ferrucci, L., Balfour, J., Chaves, P., Fried, L. P., Harris, T. B. (2001) Cardiovascular disease, interleukin-6, and risk of mortality in older women: the women’s health and aging study Circulation 103,947-953[Abstract/Free Full Text]
    24. 24
  24. Reuben, D. B., Cheh, A. I., Harris, T. B., Ferrucci, L., Rowe, J. W., Tracy, R. P., Seeman, T. E. (2002) Peripheral blood markers of inflammation predict mortality and functional decline in high-functioning community-dwelling older persons J. Am. Geriatr. Soc. 50,638-644[CrossRef][Medline]
    25. 25
  25. Roubenoff, R., Parise, H., Payette, H. A., Abad, L. W., D’Agostino, R., Jacques, P. F., Wilson, P. W., Dinarello, C. A., Harris, T. B. (2003) Cytokines, insulin-like growth factor 1, sarcopenia, and mortality in very old community-dwelling men and women: the Framingham Heart Study Am. J. Med. 115,429-435[CrossRef][Medline]
    26. 26
  26. Mooradian, A. D., Reed, R. L., Osterweil, D., Scuderi, P. (1991) Detectable serum levels of tumor necrosis factor {alpha} may predict early mortality in elderly institutionalized patients J. Am. Geriatr. Soc. 39,891-894[Medline]
    27. 27
  27. Rosenthal, A. J., McMurtry, C. T., Sanders, K. M., Jacobs, M., Thompson, D., Adler, R. A. (1997) The soluble interleukin-2 receptor predicts mortality in older hospitalized men J. Am. Geriatr. Soc. 45,1362-1364[Medline]
    28. 28
  28. Weijenberg, M. P., Feskens, E. J., Kromhout, D. (1996) White blood cell count and the risk of coronary heart disease and all-cause mortality in elderly men Arterioscler. Thromb. Vasc. Biol. 16,499-503[Abstract/Free Full Text]
    29. 29
  29. Cappola, A. R., Xue, Q. L., Ferrucci, L., Guralnik, J. M., Volpato, S., Fried, L. P. (2003) Insulin-like growth factor I and interleukin-6 contribute synergistically to disability and mortality in older women J. Clin. Endocrinol. Metab. 88,2019-2025[Abstract/Free Full Text]
    30. 30
  30. Yeh, S. S., Hafner, A., Chang, C. K., Levine, D. M., Parker, T. S., Schuster, M. W. (2004) Risk factors relating blood markers of inflammation and nutritional status to survival in cachectic geriatric patients in a randomized clinical trial J. Am. Geriatr. Soc. 52,1708-1712[CrossRef][Medline]
    31. 31
  31. Bruunsgaard, H., Andersen-Ranberg, K., Hjelmborg, J. B., Pedersen, B., Jeune, B. (2003) Elevated levels of tumor necrosis factor {alpha} and mortality in centenarians Am. J. Med. 115,278-283[CrossRef][Medline]
    32. 32
  32. Bruunsgaard, H., Ladelund, S., Pedersen, A. N., Schroll, M., Jorgensen, T., Pedersen, B. K. (2003) Predicting death from TNF-{alpha} and IL-6 in 80-year-old people Clin. Exp. Immunol. 132,24-31[CrossRef][Medline]
    33. 33
  33. Tracey, K. J. (2002) The inflammatory reflex Nature 420,853-859[CrossRef][Medline]
    34. 34
  34. Smeeth, L., Thomas, S. L., Hall, A. J., Hubbard, R., Farrington, P., Vallance, P. (2004) Risk of myocardial infarction and stroke after acute infection or vaccination N. Engl. J. Med. 351,2611-2618[Abstract/Free Full Text]
    35. 35
  35. Plomgaard, P., Keller, P., Keller, C., Pedersen, B. K. (2005) TNF-{alpha}, but not IL-6, stimulates plasminogen activator inhibitor 1 expression in human subcutaneous adipose tissue J. Appl. Physiol. 98,2019-2023[Abstract/Free Full Text]
    36. 36
  36. Gabay, C., Kushner, I. (1999) Acute-phase proteins and other systemic responses to inflammation N. Engl. J. Med. 340,448-454[Free Full Text]
    37. 37
  37. Bruunsgaard, H., Østergaard, L., Andersen-Ranberg, K., Jeune, B., Pedersen, B. K. (2002) Proinflammatory cytokines, antibodies to Chlamydia pneumoniae and age-associated diseases in Danish centenarians—is there a link? Scand. J. Infect. Dis. 34,493-499[CrossRef][Medline]
    38. 38
  38. Prio, T. K., Bruunsgaard, H., Røge, B., Skinhoj, P., Pedersen, B. K. (2002) Asymtomatic bacteriuria in elderly humans is associated with increased levels of circulating TNF receptors Exp. Gerontol. 37,693-699[CrossRef][Medline]
    39. 39
  39. Meurman, J. H., Pajukoski, H., Snellman, S., Zeiler, S., Sulkava, R. (1997) Oral infections in home-living elderly patients admitted to an acute geriatric ward J. Dent. Res. 76,1271-1276[Abstract/Free Full Text]
    40. 40
  40. Kiechl, S., Egger, G., Mayr, M., Wiedermann, C. J., Bonora, E., Oberhollenzer, F., Muggeo, M., Xu, Q., Wick, G., Poewe, W., Willeit, J. (2001) Chronic infections and the risk of carotid atherosclerosis: prospective results from a large population study Circulation 103,1064-1070[Abstract/Free Full Text]
    41. 41
  41. Dandona, P., Weinstock, R., Thusu, K., Abdel-Rahman, E., Aljada, A., Wadden, T. (1998) Tumor necrosis factor-{alpha} in sera of obese patients: fall with weight loss J. Clin. Endocrinol. Metab. 83,2907-2910[Abstract/Free Full Text]
    42. 42
  42. Weisberg, S. P., McCann, D., Desai, M., Rosenbaum, M., Leibel, R. L., Ferrante, A. W., Jr (2003) Obesity is associated with macrophage accumulation in adipose tissue J. Clin. Invest. 112,1796-1808[CrossRef][Medline]
    43. 43
  43. Xu, H., Barnes, G. T., Yang, Q., Tan, G., Yang, D., Chou, C. J., Sole, J., Nichols, A., Ross, J. S., Tartaglia, L. A., Chen, H. (2003) Chronic inflammation in fat plays a crucial role in the development of obesity-related insulin resistance J. Clin. Invest. 112,1821-1830[CrossRef][Medline]
    44. 44
  44. Uysal, K. T., Wiesbrock, S. M., Marino, M. W., Hotamisligil, G. S. (1997) Protection from obesity-induced insulin resistance in mice lacking TNF-{alpha} function Nature 389,610-614[CrossRef][Medline]
    45. 45
  45. Hotamisligil, G. S., Shargill, N. S., Spiegelman, B. M. (1993) Adipose expression of tumor necrosis factor-{alpha}: direct role in obesity-linked insulin resistance Science 259,87-91[Abstract/Free Full Text]
    46. 46
  46. Hotamisligil, G. S., Peraldi, P., Budavari, A., Ellis, R., White, M. F., Spiegelman, B. M. (1996) IRS-1-mediated inhibition of insulin receptor tyrosine kinase activity in TNF-{alpha}- and obesity-induced insulin resistance Science 271,665-668[Abstract]
    47. 47
  47. Kanety, H., Feinstein, R., Papa, M. Z., Hemi, R., Karasik, A. (1995) Tumor necrosis factor {alpha}-induced phosphorylation of insulin receptor substrate-1 (IRS-1). Possible mechanism for suppression of insulin-stimulated tyrosine phosphorylation of IRS-1 J. Biol. Chem. 270,23780-23784[Abstract/Free Full Text]
    48. 48
  48. Wellen, K. E., Hotamisligil, G. S. (2005) Inflammation, stress, and diabetes J. Clin. Invest. 115,1111-1119[CrossRef][Medline]
    49. 49
  49. Dandona, P., Aljada, A., Chaudhuri, A., Mohanty, P., Garg, R. (2005) Metabolic syndrome: a comprehensive perspective based on interactions between obesity, diabetes, and inflammation Circulation 111,1448-1454[Free Full Text]
    50. 50
  50. Hirosumi, J., Tuncman, G., Chang, L., Gorgun, C. Z., Uysal, K. T., Maeda, K., Karin, M., Hotamisligil, G. S. (2002) A central role for JNK in obesity and insulin resistance Nature 420,333-336[CrossRef][Medline]
    51. 51
  51. Arkan, M. C., Hevener, A. L., Greten, F. R., Maeda, S., Li, Z. W., Long, J. M., Wynshaw-Boris, A., Poli, G., Olefsky, J., Karin, M. (2005) IKK-ß links inflammation to obesity-induced insulin resistance Nat. Med. 11,191-198[CrossRef][Medline]
    52. 52
  52. de Alvaro, C., Teruel, T., Hernandez, R., Lorenzo, M. (2004) Tumor necrosis factor {alpha} produces insulin resistance in skeletal muscle by activation of inhibitor {kappa}B kinase in a p38 MAPK-dependent manner J. Biol. Chem. 279,17070-17078[Abstract/Free Full Text]
    53. 53
  53. Ueki, K., Kondo, T., Kahn, C. R. (2004) Suppressor of cytokine signaling 1 (SOCS-1) and SOCS-3 cause insulin resistance through inhibition of tyrosine phosphorylation of insulin receptor substrate proteins by discrete mechanisms Mol. Cell. Biol. 24,5434-5446[Abstract/Free Full Text]
    54. 54
  54. Rui, L., Yuan, M., Frantz, D., Shoelson, S., White, M. F. (2002) SOCS-1 and SOCS-3 block insulin signaling by ubiquitin-mediated degradation of IRS1 and IRS2 J. Biol. Chem. 277,42394-42398[Abstract/Free Full Text]
    55. 55
  55. Zhang, H. H., Halbleib, M., Ahmad, F., Manganiello, V. C., Greenberg, A. S. (2002) Tumor necrosis factor-{alpha} stimulates lipolysis in differentiated human adipocytes through activation of extracellular signal-related kinase and elevation of intracellular cAMP Diabetes 51,2929-2935[Abstract/Free Full Text]
    56. 56
  56. Ryden, M., Arvidsson, E., Blomqvist, L., Perbeck, L., Dicker, A., Arner, P. (2004) Targets for TNF-{alpha}-induced lipolysis in human adipocytes Biochem. Biophys. Res. Commun. 318,168-175[CrossRef][Medline]
    57. 57
  57. Khovidhunkit, W., Memon, R. A., Feingold, K. R., Grunfeld, C. (2000) Infection and inflammation-induced proatherogenic changes of lipoproteins J. Infect. Dis. 181(Suppl. 3),S462-S472
    58. 58
  58. Genctoy, G., Altun, B., Kiykim, A. A., Arici, M., Erdem, Y., Caglarg, M., Yasavul, U., Turgan, C., Caglar, S. (2005) TNF {alpha}-308 genotype and renin-angiotensin system in hemodialysis patients: an effect on inflammatory cytokine levels? Artif. Organs 29,174-178[CrossRef][Medline]
    59. 59
  59. Ross, R. (1999) Atherosclerosis—an inflammatory disease N. Engl. J. Med. 340,115-126[Free Full Text]
    60. 60
  60. Meager, A. (1999) Cytokine regulation of cellular adhesion molecule expression in inflammation Cytokine Growth Factor Rev. 10,27-39[CrossRef][Medline]
    61. 61
  61. Bhagat, K., Vallance, P. (1997) Inflammatory cytokines impair endothelium-dependent dilatation in human veins in vivo Circulation 96,3042-3047[Abstract/Free Full Text]
    62. 62
  62. Antoniades, C., Tousoulis, D., Vasiliadou, C., Marinou, K., Tentolouris, C., Ntarladimas, I., Stefanadis, C. (2004) Combined effects of smoking and hypercholesterolemia on inflammatory process, thrombosis/fibrinolysis system, and forearm hyperemic response Am. J. Cardiol. 94,1181-1184[CrossRef][Medline]
    63. 63
  63. Sethi, S. (2004) New developments in the pathogenesis of acute exacerbations of chronic obstructive pulmonary disease Curr. Opin. Infect. Dis. 17,113-119[CrossRef][Medline]
    64. 64
  64. de Godoy, I., Donahoe, M., Calhoun, W. J., Mancino, J., Rogers, R. M. (1996) Elevated TNF-{alpha} production by peripheral blood monocytes of weight-losing COPD patients Am. J. Respir. Crit. Care Med. 153,633-637[Abstract]
    65. 65
  65. Schols, A. M., Buurman, W. A., Staal van den Brekel, A. J., Dentener, M. A., Wouters, E. F. (1996) Evidence for a relation between metabolic derangements and increased levels of inflammatory mediators in a subgroup of patients with chronic obstructive pulmonary disease Thorax 51,819-824[Abstract/Free Full Text]
    66. 66
  66. Roubenoff, R., Grinspoon, S., Skolnik, P. R., Tchetgen, E., Abad, L., Spiegelman, D., Knox, T., Gorbach, S. (2002) Role of cytokines and testosterone in regulating lean body mass and resting energy expenditure in HIV-infected men Am. J. Physiol. Endocrinol. Metab. 283,E138-E145[Abstract/Free Full Text]
    67. 67
  67. Hoshino, E., Pichard, C., Greenwood, C. E., Kuo, G. C., Cameron, R. G., Kurian, R., Kearns, J. P., Allard, J. P., Jeejeebhoy, K. N. (1991) Body composition and metabolic rate in rat during a continuous infusion of cachectin Am. J. Physiol. 260,E27-E36
    68. 68
  68. Reid, M. B., Li, Y. P. (2001) Tumor necrosis factor-{alpha} and muscle wasting: a cellular perspective Respir. Res. 2,269-272[CrossRef][Medline]
    69. 69
  69. Visser, M., Pahor, M., Taaffe, D. R., Goodpaster, B. H., Simonsick, E. M., Newman, A. B., Nevitt, M., Harris, T. B. (2002) Relationship of interleukin-6 and tumor necrosis factor-{alpha} with muscle mass and muscle strength in elderly men and women: the Health ABC Study J. Gerontol. A Biol. Sci. Med. Sci. 57,M326-M332[Abstract/Free Full Text]
    70. 70
  70. Cesari, M., Penninx, B. W., Pahor, M., Lauretani, F., Corsi, A. M., Rhys, W. G., Guralnik, J. M., Ferrucci, L. (2004) Inflammatory markers and physical performance in older persons: the InCHIANTI study J. Gerontol. A Biol. Sci. Med. Sci. 59,242-248
    71. 71
  71. Greiwe, J. S., Cheng, B., Rubin, D. C., Yarasheski, K. E., Semenkovich, C. F. (2001) Resistance exercise decreases skeletal muscle tumor necrosis factor {alpha} in frail elderly humans FASEB J. 15,475-482[Abstract/Free Full Text]
    72. 72
  72. Bernard, V., Pillois, X., Dubus, I., Benchimol, D., Labouyrie, J. P., Couffinhal, T., Coste, P., Bonnet, J. (2003) The –308 G/A tumor necrosis factor-{alpha} gene dimorphism: a risk factor for unstable angina Clin. Chem. Lab. Med. 41,511-516[CrossRef][Medline]
    73. 73
  73. Kubaszek, A., Pihlajamaki, J., Komarovski, V., Lindi, V., Lindstrom, J., Eriksson, J., Valle, T. T., Hamalainen, H., Ilanne-Parikka, P., Keinanen-Kiukaanniemi, S., Tuomilehto, J., Uusitupa, M., Laakso, M. (2003) Promoter polymorphisms of the TNF-{alpha} (G-308A) and IL-6 (C-174G) genes predict the conversion from impaired glucose tolerance to type 2 diabetes: the Finnish Diabetes Prevention Study Diabetes 52,1872-1876[Abstract/Free Full Text]
    74. 74
  74. Heijmans, B. T., Westendorp, R. G., Droog, S., Kluft, C., Knook, D. L., Slagboom, P. E. (2002) Association of the tumour necrosis factor {alpha} –308G/A polymorphism with the risk of diabetes in an elderly population-based cohort Genes Immun. 3,225-228[CrossRef][Medline]
    75. 75
  75. Dalziel, B., Gosby, A. K., Richman, R. M., Bryson, J. M., Caterson, I. D. (2002) Association of the TNF-{alpha} –308 G/A promoter polymorphism with insulin resistance in obesity Obes. Res. 10,401-407[Medline]
    76. 76
  76. Nicaud, V., Raoux, S., Poirier, O., Cambien, F., O’Reilly, D. S., Tiret, L. (2002) The TNF{alpha}/G-308A polymorphism influences insulin sensitivity in offspring of patients with coronary heart disease. The European Atherosclerosis Research Study II Atherosclerosis 161,317-325[CrossRef][Medline]
    77. 77
  77. Vendrell, J., Fernandez-Real, J. M., Gutierrez, C., Zamora, A., Simon, I., Bardaji, A., Ricart, W., Richart, C. (2003) A polymorphism in the promoter of the tumor necrosis factor-{alpha} gene (–308) is associated with coronary heart disease in type 2 diabetic patients Atherosclerosis 167,257-264[CrossRef][Medline]
    78. 78
  78. Jaattela, M. (1991) Biologic activities and mechanisms of action of tumor necrosis factor-{alpha}/cachectin Lab. Invest. 64,724-742[Medline]
    79. 79
  79. Saves, M., Morlat, P., Chene, G., Peuchant, E., Pellegrin, I., Bonnet, F., Bernard, N., Lacoste, D., Salamon, R., Beylot, J. (2001) Prognostic value of plasma markers of immune activation in patients with advanced HIV disease treated by combination antiretroviral therapy Clin. Immunol. 99,347-352[CrossRef][Medline]
    80. 80
  80. Ferrari, R., Bachetti, T., Confortini, R., Opasich, C., Febo, O., Corti, A., Cassani, G., Visioli, O. (1995) Tumor necrosis factor soluble receptors in patients with various degrees of congestive heart failure Circulation 92,1479-1486[Abstract/Free Full Text]
    81. 81
  81. Zee, R. Y., Ridker, P. M. (2002) Polymorphism in the human C-reactive protein (CRP) gene, plasma concentrations of CRP, and the risk of future arterial thrombosis Atherosclerosis 162,217-219[CrossRef][Medline]
    82. 82
  82. Suk, H. J., Ridker, P. M., Cook, N. R., Zee, R. Y. (2005) Relation of polymorphism within the C-reactive protein gene and plasma CRP levels Atherosclerosis 178,139-145[CrossRef][Medline]
    83. 83
  83. Van Den Biggelaar, A. H., De Craen, A. J., Gussekloo, J., Huizinga, T. W., Heijmans, B. T., Frolich, M., Kirkwood, T. B., Westendorp, R. G. (2004) Inflammation underlying cardiovascular mortality is a late consequence of evolutionary programming FASEB J. 18,1022-1024[Abstract/Free Full Text]
    84. 84
  84. Hu, F. B., Willett, W. C., Li, T., Stampfer, M. J., Colditz, G. A., Manson, J. E. (2004) Adiposity as compared with physical activity in predicting mortality among women N. Engl. J. Med. 351,2694-2703[Abstract/Free Full Text]
    85. 85
  85. Manson, J. E., Greenland, P., LaCroix, A. Z., Stefanick, M. L., Mouton, C. P., Oberman, A., Perri, M. G., Sheps, D. S., Pettinger, M. B., Siscovick, D. S. (2002) Walking compared with vigorous exercise for the prevention of cardiovascular events in women N. Engl. J. Med. 347,716-725[Abstract/Free Full Text]
    86. 86
  86. Knowler, W. C., Barrett-Connor, E., Fowler, S. E., Hamman, R. F., Lachin, J. M., Walker, E. A., Nathan, D. M. (2002) Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin N. Engl. J. Med. 346,393-403[Abstract/Free Full Text]
    87. 87
  87. Samad, A. K., Taylor, R. S., Marshall, T., Chapman, M. A. (2005) A meta-analysis of the association of physical activity with reduced risk of colorectal cancer Colorectal Dis. 7,204-213[CrossRef][Medline]
    88. 88
  88. Holmes, M. D., Chen, W. Y., Feskanich, D., Kroenke, C. H., Colditz, G. A. (2005) Physical activity and survival after breast cancer diagnosis JAMA 293,2479-2486[Abstract/Free Full Text]
    89. 89
  89. van Gelder, B. M., Tijhuis, M. A., Kalmijn, S., Giampaoli, S., Nissinen, A., Kromhout, D. (2004) Physical activity in relation to cognitive decline in elderly men: the FINE Study Neurology 63,2316-2321[Abstract/Free Full Text]
    90. 90
  90. Weuve, J., Kang, J. H., Manson, J. E., Breteler, M. M., Ware, J. H., Grodstein, F. (2004) Physical activity, including walking, and cognitive function in older women JAMA 292,1454-1461[Abstract/Free Full Text]
    91. 91
  91. Abbott, R. D., White, L. R., Ross, G. W., Masaki, K. H., Curb, J. D., Petrovitch, H. (2004) Walking and dementia in physically capable elderly men JAMA 292,1447-1453[Abstract/Free Full Text]
    92. 92
  92. Blair, S. N., Cheng, Y., Holder, J. S. (2001) Is physical activity or physical fitness more important in defining health benefits? Med. Sci. Sports Exerc. 33,S379-S399[CrossRef][Medline]
    93. 93
  93. Taylor, R. S., Brown, A., Ebrahim, S., Jolliffe, J., Noorani, H., Rees, K., Skidmore, B., Stone, J. A., Thompson, D. R., Oldridge, N. (2004) Exercise-based rehabilitation for patients with coronary heart disease: systematic review and meta-analysis of randomized controlled trials Am. J. Med. 116,682-692[CrossRef][Medline]
    94. 94
  94. Piepoli, M. F., Davos, C., Francis, D. P., Coats, A. J. (2004) Exercise training meta-analysis of trials in patients with chronic heart failure (ExTraMATCH) BMJ 328,189[Abstract/Free Full Text]
    95. 95
  95. Boule, N. G., Haddad, E., Kenny, G. P., Wells, G. A., Sigal, R. J. (2001) Effects of exercise on glycemic control and body mass in type 2 diabetes mellitus: a meta-analysis of controlled clinical trials JAMA 286,1218-1227[Abstract/Free Full Text]
    96. 96
  96. Lacasse, Y., Brosseau, L., Milne, S., Martin, S., Wong, E., Guyatt, G. H., Goldstein, R. S. (2002) Pulmonary rehabilitation for chronic obstructive pulmonary disease Cochrane Database Syst. Rev. CD003793
    97. 97
  97. Panagiotakos, D. B., Pitsavos, C., Chrysohoou, C., Kavouras, S., Stefanadis, C. (2005) The associations between leisure-time physical activity and inflammatory and coagulation markers related to cardiovascular disease: the ATTICA Study Prev. Med. 40,432-437[CrossRef][Medline]
    98. 98
  98. Pitsavos, C., Panagiotakos, D. B., Chrysohoou, C., Kavouras, S., Stefanadis, C. (2005) The associations between physical activity, inflammation, and coagulation markers, in people with metabolic syndrome: the ATTICA study Eur. J. Cardiovasc. Prev. Rehabil. 12,151-158[CrossRef][Medline]
    99. 99
  99. Colbert, L. H., Visser, M., Simonsick, E. M., Tracy, R. P., Newman, A. B., Kritchevsky, S. B., Pahor, M., Taaffe, D. R., Brach, J., Rubin, S., Harris, T. B. (2004) Physical activity, exercise, and inflammatory markers in older adults: findings from the health, aging and body composition study J. Am. Geriatr. Soc. 52,1098-1104[CrossRef][Medline]
    100. 100
  100. Stauffer, B. L., Hoetzer, G. L., Smith, D. T., DeSouza, C. A. (2004) Plasma C-reactive protein is not elevated in physically active postmenopausal women taking hormone replacement therapy J. Appl. Physiol. 96,143-148[Abstract/Free Full Text]
    101. 101
  101. King, D. E., Carek, P., Mainous, A. G., III, Pearson, W. S. (2003) Inflammatory markers and exercise: differences related to exercise type Med. Sci. Sports Exerc. 35,575-581[CrossRef][Medline]
    102. 102
  102. Manns, P. J., Williams, D. P., Snow, C. M., Wander, R. C. (2003) Physical activity, body fat, and serum C-reactive protein in postmenopausal women with and without hormone replacement Am. J. Hum. Biol. 15,91-100[CrossRef][Medline]
    103. 103
  103. Reuben, D. B., Judd-Hamilton, L., Harris, T. B., Seeman, T. E. (2003) The associations between physical activity and inflammatory markers in high-functioning older persons: MacArthur studies of successful aging J. Am. Geriatr. Soc. 51,1125-1130[CrossRef][Medline]
    104. 104
  104. Jankord, R., Jemiolo, B. (2004) Influence of physical activity on serum IL-6 and IL-10 levels in healthy older men Med. Sci. Sports Exerc. 36,960-964[CrossRef][Medline]
    105. 105
  105. Dufaux, B., Order, U., Geyer, H., Hollmann, W. (1984) C-reactive protein serum concentrations in well-trained athletes Int. J. Sports Med. 5,102-106[Medline]
    106. 106
  106. Tomaszewski, M., Charchar, F. J., Przybycin, M., Crawford, L., Wallace, A. M., Gosek, K., Lowe, G. D., Zukowska-Szczechowska, E., Grzeszczak, W., Sattar, N., Dominiczak, A. F. (2003) Strikingly low circulating CRP concentrations in ultramarathon runners independent of markers of adiposity: how low can you go? Arterioscler. Thromb. Vasc. Biol. 23,1640-1644[Abstract/Free Full Text]
    107. 107
  107. Fredrikson, G. N., Hedblad, B., Nilsson, J. A., Alm, R., Berglund, G., Nilsson, J. (2004) Association between diet, lifestyle, metabolic cardiovascular risk factors, and plasma C-reactive protein levels Metabolism 53,1436-1442[CrossRef][Medline]
    108. 108
  108. Verdaet, D., Dendale, P., De Bacquer, D., Delanghe, J., Block, P., De Backer, G. (2004) Association between leisure time physical activity and markers of chronic inflammation related to coronary heart disease Atherosclerosis 176,303-310[CrossRef][Medline]
    109. 109
  109. Rawson, E. S., Freedson, P. S., Osganian, S. K., Matthews, C. E., Reed, G., Ockene, I. S. (2003) Body mass index, but not physical activity, is associated with C-reactive protein Med. Sci. Sports Exerc. 35,1160-1166[CrossRef][Medline]
    110. 110
  110. Goldhammer, E., Tanchilevitch, A., Maor, I., Beniamini, Y., Rosenschein, U., Sagiv, M. (2005) Exercise training modulates cytokines activity in coronary heart disease patients Int. J. Cardiol. 100,93-99[CrossRef][Medline]
    111. 111
  111. Tisi, P. V., Hulse, M., Chulakadabba, A., Gosling, P., Shearman, C. P. (1997) Exercise training for intermittent claudication: does it adversely affect biochemical markers of the exercise-induced inflammatory response? Eur. J. Vasc. Endovasc. Surg. 14,344-350[CrossRef][Medline]
    112. 112
  112. Adamopoulos, S., Parissis, J., Kroupis, C., Georgiadis, M., Karatzas, D., Karavolias, G., Koniavitou, K., Coats, A. J., Kremastinos, D. T. (2001) Physical training reduces peripheral markers of inflammation in patients with chronic heart failure Eur. Heart J. 22,791-797[Abstract/Free Full Text]
    113. 113
  113. Gielen, S., Adams, V., Mobius-Winkler, S., Linke, A., Erbs, S., Yu, J., Kempf, W., Schubert, A., Schuler, G., Hambrecht, R. (2003) Anti-inflammatory effects of exercise training in the skeletal muscle of patients with chronic heart failure J. Am. Coll. Cardiol. 42,861-868[Abstract/Free Full Text]
    114. 114
  114. Larsen, A. I., Aukrust, P., Aarsland, T., Dickstein, K. (2001) Effect of aerobic exercise training on plasma levels of tumor necrosis factor {alpha} in patients with heart failure Am. J. Cardiol. 88,805-808[CrossRef][Medline]
    115. 115
  115. Conraads, V. M., Beckers, P., Bosmans, J., De Clerck, L. S., Stevens, W. J., Vrints, C. J., Brutsaert, D. L. (2002) Combined endurance/resistance training reduces plasma TNF-{alpha} receptor levels in patients with chronic heart failure and coronary artery disease Eur. Heart J. 23,1854-1860[Abstract/Free Full Text]
    116. 116
  116. Mattusch, F., Dufaux, B., Heine, O., Mertens, I., Rost, R. (2000) Reduction of the plasma concentration of C-reactive protein following nine months of endurance training Int. J. Sports Med. 21,21-24[CrossRef][Medline]
    117. 117
  117. Volpato, S., Pahor, M., Ferrucci, L., Simonsick, E. M., Guralnik, J. M., Kritchevsky, S. B., Fellin, R., Harris, T. B. (2004) Relationship of alcohol intake with inflammatory markers and plasminogen activator inhibitor-1 in well-functioning older adults: the health, aging, and body composition study Circulation 109,607-612[Abstract/Free Full Text]
    118. 118
  118. Nicklas, B. J., Ambrosius, W., Messier, S. P., Miller, G. D., Penninx, B. W., Loeser, R. F., Palla, S., Bleecker, E., Pahor, M. (2004) Diet-induced weight loss, exercise, and chronic inflammation in older, obese adults: a randomized controlled clinical trial Am. J. Clin. Nutr. 79,544-551[Abstract/Free Full Text]
    119. 119
  119. Bruunsgaard, H., Bjerregaard, E., Schroll, M., Pedersen, B. K. (2004) Muscle strength after resistance training is inversely correlated with baseline levels of soluble tumor necrosis factor receptors in the oldest old J. Am. Geriatr. Soc. 52,237-241[CrossRef][Medline]
    120. 120
  120. Ferrier, K. E., Nestel, P., Taylor, A., Drew, B. G., Kingwell, B. A. (2004) Diet but not aerobic exercise training reduces skeletal muscle TNF-{alpha} in overweight humans Diabetologia 47,630-637[CrossRef][Medline]
    121. 121
  121. Ostrowski, K., Rohde, T., Zacho, M., Asp, S., Pedersen, B. K. (1998) Evidence that interleukin-6 is produced in human skeletal muscle during prolonged running J. Physiol. 508,949-953[Abstract/Free Full Text]
    122. 122
  122. Ostrowski, K., Hermann, C., Bangash, A., Schjerling, P., Nielsen, J. N., Pedersen, B. K. (1998) A trauma-like elevation of plasma cytokines in humans in response to treadmill running J. Physiol. 513,889-894[Abstract/Free Full Text]
    123. 123
  123. Ostrowski, K., Rohde, T., Asp, S., Schjerling, P., Pedersen, B. K. (1999) Pro- and anti-inflammatory cytokine balance in strenuous exercise in humans J. Physiol. 515,287-291[Abstract/Free Full Text]
    124. 124
  124. Bruunsgaard, H., Galbo, H., Halkjaer-Kristensen, J., Johansen, T. L., MacLean, D. A., Pedersen, B. K. (1997) Exercise induced increase in serum interleukin 6 in humans is related to muscle damage J. Physiol. 499,833-841[Abstract/Free Full Text]
    125. 125
  125. Croisier, J. L., Camus, G., Venneman, I., Deby-Dupont, G., Juchmes-Ferir, A., Lamy, M., Crielaard, J. M., Deby, C., Duchateau, J. (1999) Effects of training on exercise-induced muscle damage and interleukin 6 production Muscle Nerve 22,208-212[CrossRef][Medline]
    126. 126
  126. Steensberg, A., Febbraio, M. A., Osada, T., Schjerling, P., van Hall, G., Saltin, B., Pedersen, B. K. (2001) Interleukin-6 production in contracting human skeletal muscle is influenced by pre-exercise muscle glycogen content J. Physiol. 537,633-639[Abstract/Free Full Text]
    127. 127
  127. Starkie, R. L., Rolland, J., Angus, D. J., Anderson, M. J., Febbraio, M. A. (2001) Circulating monocytes are not the source of elevations in plasma IL-6 and TNF-{alpha} levels after prolonged running Am. J. Physiol. Cell Physiol. 280,C769-C774[Abstract/Free Full Text]
    128. 128
  128. Saghizadeh, M., Ong, J. M., Garvey, W. T., Henry, R. R., Kern, P. A. (1996) The expression of TNF {alpha} by human muscle. Relationship to insulin resistance J. Clin. Invest. 97,1111-1116[Medline]
    129. 129
  129. De Rossi, M., Bernasconi, P., Baggi, F., de Waal, M. R., Mantegazza, R. (2000) Cytokines and chemokines are both expressed by human myoblasts: possible relevance for the immune pathogenesis of muscle inflammation Int. Immunol. 12,1329-1335[Abstract/Free Full Text]
    130. 130
  130. Alvarez, B., Quinn, L. S., Busquets, S., Lopez-Soriano, F. J., Argiles, J. M. (2002) TNF-{alpha} modulates cytokine and cytokine receptors in C2C12 myotubes Cancer Lett. 175,181-185[CrossRef][Medline]
    131. 131
  131. Starkie, R. L., Arkinstall, M. J., Koukoulas, I., Hawley, J. A., Febbraio, M. A. (2001) Carbohydrate ingestion attenuates the increase in plasma interleukin-6, but not skeletal muscle interleukin-6 mRNA, during exercise in humans J. Physiol. 533,585-591[Abstract/Free Full Text]
    132. 132
  132. Keller, C., Steensberg, A., Pilegaard, H., Osada, T., Saltin, B., Pedersen, B. K., Neufer, P. D. (2001) Transcriptional activation of the IL-6 gene in human contracting skeletal muscle: influence of muscle glycogen content FASEB J. 15,2748-2750[Free Full Text]
    133. 133
  133. Jonsdottir, I. H., Schjerling, P., Ostrowski, K., Asp, S., Richter, E. A., Pedersen, B. K. (2000) Muscle contractions induce interleukin-6 mRNA production in rat skeletal muscles J. Physiol. 528,157-163[Abstract/Free Full Text]
    134. 134
  134. Steensberg, A., van Hall, G., Osada, T., Sacchetti, M., Saltin, B., Klarlund, P. B. (2000) Production of interleukin-6 in contracting human skeletal muscles can account for the exercise-induced increase in plasma interleukin-6 J. Physiol. 529,237-242[Abstract/Free Full Text]
    135. 135
  135. Penkowa, M., Keller, C., Keller, P., Jauffred, S., Pedersen, B. K. (2003) Immunohistochemical detection of interleukin-6 in human skeletal muscle fibers following exercise FASEB J. 17,2166-2168[Abstract/Free Full Text]
    136. 136
  136. Hiscock, N., Chan, M. H., Bisucci, T., Darby, I. A., Febbraio, M. A. (2004) Skeletal myocytes are a source of interleukin-6 mRNA expression and protein release during contraction: evidence of fiber-type specificity FASEB J. 18,992-994[Abstract/Free Full Text]
    137. 137
  137. Fischer, C. P., Hiscock, N. J., Penkowa, M., Basu, S., Vessby, B., Kallner, A., Sjoberg, L. B., Pedersen, B. K. (2004) Supplementation with vitamins C and E inhibits the release of interleukin-6 from contracting human skeletal muscle J. Physiol. 558,633-645[Abstract/Free Full Text]
    138. 138
  138. Keller, C., Keller, P., Marshal, S., Pedersen, B. K. (2003) IL-6 gene expression in human adipose tissue in response to exercise—effect of carbohydrate ingestion J. Physiol. 550,927-931[Abstract/Free Full Text]
    139. 139
  139. Nybo, L., Nielsen, B., Pedersen, B. K., Moller, K., Secher, N. H. (2002) Interleukin-6 release from the human brain during prolonged exercise J. Physiol. 542,991-995[Abstract/Free Full Text]
    140. 140
  140. Langberg, H., Olesen, J. L., Gemmer, C., Kjaer, M. (2002) Substantial elevation of interleukin-6 concentration in peritendinous tissue, in contrast to muscle, following prolonged exercise in humans J. Physiol. 542,985-990[Abstract/Free Full Text]
    141. 141
  141. Nieman, D. C., Davis, J. M., Henson, D. A., Walberg-Rankin, J., Shute, M., Dumke, C. L., Utter, A. C., Vinci, D. M., Carson, J. A., Brown, A., Lee, W. J., McAnulty, S. R., McAnulty, L. S. (2003) Carbohydrate ingestion influences skeletal muscle cytokine mRNA and plasma cytokine levels after a 3-h run J. Appl. Physiol. 94,1917-1925[Abstract/Free Full Text]
    142. 142
  142. Nieman, D. C., Davis, J. M., Brown, V. A., Henson, D. A., Dumke, C. L., Utter, A. C., Vinci, D. M., Downs, M. F., Smith, J. C., Carson, J., Brown, A., McAnulty, S. R., McAnulty, L. S. (2004) Influence of carbohydrate ingestion on immune changes after 2 h of intensive resistance training J. Appl. Physiol. 96,1292-1298[Abstract/Free Full Text]
    143. 143
  143. Nehlsen-Cannarella, S. L., Fagoaga, O. R., Nieman, D. C., Henson, D. A., Butterworth, D. E., Schmitt, R. L., Bailey, E. M., Warren, B. J., Utter, A., Davis, J. M. (1997) Carbohydrate and the cytokine response to 2.5 h of running J. Appl. Physiol. 82,1662-1667[Abstract/Free Full Text]
    144. 144
  144. Steensberg, A., van Hall, G., Keller, C., Osada, T., Schjerling, P., Pedersen, B. K., Saltin, B., Febbraio, M. A. (2002) Muscle glycogen content and glucose uptake during exercise in humans: influence of prior exercise and dietary manipulation J. Physiol. 541,273-281[Abstract/Free Full Text]
    145. 145
  145. Pedersen, M., Steensberg, A., Keller, C., Osada, T., Zacho, M., Saltin, B., Febbraio, M. A., Pedersen, B. K. (2004) Does the aging skeletal muscle maintain its endocrine function? Exerc. Immunol. Rev. 10,42-55[Medline]
    146. 146
  146. Febbraio, M. A., Steensberg, A., Starkie, R. L., McConell, G. K., Kingwell, B. A. (2003) Skeletal muscle interleukin-6 and tumor necrosis factor-{alpha} release in healthy subjects and patients with type 2 diabetes at rest and during exercise Metabolism 52,939-944[CrossRef][Medline]
    147. 147
  147. Hamada, K., Vannier, E., Sacheck, J. M., Witsell, A. L., Roubenoff, R. (2005) Senescence of human skeletal muscle impairs the local inflammatory cytokine response to acute eccentric exercise FASEB J. 19,264-266[Abstract/Free Full Text]
    148. 148
  148. Toft, A. D., Jensen, L. B., Bruunsgaard, H., Ibfelt, T., Halkjaer-Kristensen, J., Febbraio, M., Pedersen, B. K. (2002) Cytokine response to eccentric exercise in young and elderly humans Am. J. Physiol. Cell Physiol. 283,C289-C295[Abstract/Free Full Text]
    149. 149
  149. Steensberg, A., Keller, C., Starkie, R. L., Osada, T., Febbraio, M. A., Pedersen, B. K. (2002) IL-6 and TNF-{alpha} expression in, and release from, contracting human skeletal muscle Am. J. Physiol. Endocrinol. Metab. 283,E1272-E1278[Abstract/Free Full Text]
    150. 150
  150. Akerstrom, T., Steensberg, A., Keller, P., Keller, C., Penkowa, M., Pedersen, B. K. (2005) Exercise induces interleukin-8 expression in human skeletal muscle J. Physiol. 563,507-516[Abstract/Free Full Text]
    151. 151
  151. Chan, M. H., Carey, A. L., Watt, M. J., Febbraio, M. A. (2004) Cytokine gene expression in human skeletal muscle during concentric contraction: evidence that IL-8, like IL-6, is influenced by glycogen availability Am. J. Physiol. Regul. Integr. Comp. Physiol. 287,R322-R327[Abstract/Free Full Text]
    152. 152
  152. Ostrowski, K., Rohde, T., Asp, S., Schjerling, P., Pedersen, B. K. (2001) Chemokines are elevated in plasma after strenuous exercise in humans Eur. J. Appl. Physiol. 84,244-245[CrossRef][Medline]
    153. 153
  153. Suzuki, K., Nakaji, S., Yamada, M., Liu, Q., Kurakake, S., Okamura, N., Kumae, T., Umeda, T., Sugawara, K. (2003) Impact of a competitive marathon race on systemic cytokine and neutrophil responses Med. Sci. Sports Exerc. 35,348-355[CrossRef][Medline]
    154. 154
  154. Grabstein, K. H., Eisenman, J., Shanebeck, K., Rauch, C., Srinivasan, S., Fung, V., Beers, C., Richardson, J., Schoenborn, M. A., Ahdieh, M. (1994) Cloning of a T cell growth factor that interacts with the ß chain of the interleukin-2 receptor Science 264,965-968[Abstract/Free Full Text]
    155. 155
  155. Quinn, L. S., Haugk, K. L., Grabstein, K. H. (1995) Interleukin-15: a novel anabolic cytokine for skeletal muscle Endocrinology 136,3669-3672[Abstract]
    156. 156
  156. Riechman, S. E., Balasekaran, G., Roth, S. M., Ferrell, R. E. (2004) Association of interleukin-15 protein and interleukin-15 receptor genetic variation with resistance exercise training responses J. Appl. Physiol. 97,2214-2219[Abstract/Free Full Text]
    157. 157
  157. Delaigle, A. M., Jonas, J. C., Bauche, I. B., Cornu, O., Brichard, S. M. (2004) Induction of adiponectin in skeletal muscle by inflammatory cytokines: in vivo and in vitro studies Endocrinology 145,5589-5597[Abstract/Free Full Text]
    158. 158
  158. Pilegaard, H., Keller, C., Steensberg, A., Helge, J. W., Pedersen, B. K., Saltin, B., Neufer, P. D. (2002) Influence of pre-exercise muscle glycogen content on exercise-induced transcriptional regulation of metabolic genes J. Physiol. 541,261-271[Abstract/Free Full Text]
    159. 159
  159. Pedersen, B. K., Steensberg, A., Fischer, C., Keller, C., Keller, P., Plomgaard, P., Febbraio, M., Saltin, B. (2003) Searching for the exercise factor: is IL-6 a candidate? J. Muscle Res. Cell Motil. 24,113-119[CrossRef][Medline]
    160. 160
  160. Petersen, E. W., Carey, A. L., Sacchetti, M., Steinberg, G. R., Macaulay, S. L., Febbraio, M. A., Pedersen, B. K. (2005) Acute IL-6 treatment increases fatty acid turnover in elderly humans in vivo and in tissue culture in vitro Am. J. Physiol. Endocrinol. Metab. 288,E155-E162[Abstract/Free Full Text]
    161. 161
  161. van Hall, G., Steensberg, A., Sacchetti, M., Fischer, C., Keller, C., Schjerling, P., Hiscock, N., Moller, K., Saltin, B., Febbraio, M. A., Pedersen, B. K. (2003) Interleukin-6 stimulates lipolysis and fat oxidation in humans J. Clin. Endocrinol. Metab. 88,3005-3010[Abstract/Free Full Text]
    162. 162
  162. Stouthard, J. M., Romijn, J. A., van der Poll, T., Endert, E., Klein, S., Bakker, P. J., Veenhof, C. H., Sauerwein, H. P. (1995) Endocrinologic and metabolic effects of interleukin-6 in humans Am. J. Physiol. 268,E813-E819
    163. 163
  163. Bruce, C. R., Dyck, D. J. (2004) Cytokine regulation of skeletal muscle fatty acid metabolism: effect of interleukin-6 and tumor necrosis factor-{alpha} Am. J. Physiol. Endocrinol. Metab. 287,E616-E621[Abstract/Free Full Text]
    164. 164
  164. Febbraio, M. A., Hiscock, N., Sacchetti, M., Fischer, C. P., Pedersen, B. K. (2004) Interleukin-6 is a novel factor mediating glucose homeostasis during skeletal muscle contraction Diabetes 53,1643-1648[Abstract/Free Full Text]
    165. 165
  165. Koenig, W., Lowel, H., Baumert, J., Meisinger, C. (2004) C-reactive protein modulates risk prediction based on the Framingham score: implications for future risk assessment: results from a large cohort study in southern Germany Circulation 109,1349-1353[Abstract/Free Full Text]
    166. 166
  166. Ruderman, N. B., Saha, A. K., Kraegen, E. W. (2003) Minireview: malonyl CoA, AMP-activated protein kinase, and adiposity Endocrinology 144,5166-5171[Abstract/Free Full Text]
    167. 167
  167. Kelly, M., Keller, C., Avilucea, P. R., Keller, P., Luo, Z., Xiang, X., Giralt, M., Hidalgo, J., Saha, A. K., Pedersen, B. K., Ruderman, N. B. (2004) AMPK activity is diminished in tissues of IL-6 knockout mice: the effect of exercise Biochem. Biophys. Res. Commun. 320,449-454[CrossRef][Medline]
    168. 168
  168. Keller, P., Keller, C., Carey, A. L., Jauffred, S., Fischer, C. P., Steensberg, A., Pedersen, B. K. (2003) Interleukin-6 production by contracting human skeletal muscle: autocrine regulation by IL-6 Biochem. Biophys. Res. Commun. 310,550-554[CrossRef][Medline]
    169. 169
  169. Path, G., Bornstein, S. R., Gurniak, M., Chrousos, G. P., Scherbaum, W. A., Hauner, H. (2001) Human breast adipocytes express interleukin-6 (IL-6) and its receptor system: increased IL-6 production by ß-adrenergic activation and effects of IL-6 on adipocyte function J. Clin. Endocrinol. Metab. 86,2281-2288[Abstract/Free Full Text]
    170. 170
  170. Bauer, J., Bauer, T. M., Kalb, T., Taga, T., Lengyel, G., Hirano, T., Kishimoto, T., Acs, G., Mayer, L., Gerok, W. (1989) Regulation of interleukin 6 receptor expression in human monocytes and monocyte-derived macrophages. Comparison with the expression in human hepatocytes J. Exp. Med. 170,1537-1549[Abstract/Free Full Text]
    171. 171
  171. Lutticken, C., Wegenka, U. M., Yuan, J., Buschmann, J., Schindler, C., Ziemiecki, A., Harpur, A. G., Wilks, A. F., Yasukawa, K., Taga, T. (1994) Association of transcription factor APRF and protein kinase Jak1 with the interleukin-6 signal transducer gp130 Science 263,89-92[Abstract/Free Full Text]
    172. 172
  172. Saito, M., Yoshida, K., Hibi, M., Taga, T., Kishimoto, T. (1992) Molecular cloning of a murine IL-6 receptor-associated signal transducer, gp130, and its regulated expression in vivo J. Immunol. 148,4066-4071[Abstract]
    173. 173
  173. Keller, P., Penkowa, M., Keller, C., Steensberg, A., Fischer, C. P., Giralt, M., Hidalgo, J., Klarlund, P. B. (2005) Interleukin-6 receptor expression in contracting human skeletal muscle: regulating role of IL-6 FASEB J. 19,1181-1183[Abstract/Free Full Text]
    174. 174
  174. Keller, P., Keller, C., Robinson, L. E., Pedersen, B. K. (2004) Epinephrine infusion increases adipose interleukin-6 gene expression and systemic levels in humans J. Appl. Physiol. 97,1309-1312[Abstract/Free Full Text]
    175. 175
  175. Petersen, A. M., Pedersen, B. K. (2005) The anti-inflammatory effect of exercise J. Appl. Physiol. 98,1154-1162[Abstract/Free Full Text]
    176. 176
  176. Kolling, U. K., Hansen, F., Braun, J., Rink, L., Katus, H. A., Dalhoff, K. (2001) Leucocyte response and anti-inflammatory cytokines in community acquired pneumonia Thorax 56,121-125[Abstract/Free Full Text]
    177. 177
  177. Pedersen, B. K., Bruunsgaard, H., Klokker, M., Kappel, M., MacLean, D. A., Nielsen, H. B., Rohde, T., Ullum, H., Zacho, M. (1997) Exercise-induced immunomodulation—possible roles of neuroendocrine and metabolic factors Int. J. Sports Med. 18(Suppl. 1),S2-S7
    178. 178
  178. Henson, D. A., Nieman, D. C., Pistilli, E. E., Schilling, B., Colacino, A., Utter, A. C., Fagoaga, O. R., Vinci, D. M., Nehlsen-Cannarella, S. L. (2004) Influence of carbohydrate and age on lymphocyte function following a marathon Int. J. Sport Nutr. Exerc. Metab. 14,308-322[Medline]
    179. 179
  179. Tilg, H., Dinarello, C. A., Mier, J. W. (1997) IL-6 and APPs: anti-inflammatory and immunosuppressive mediators Immunol. Today 18,428-432[CrossRef][Medline]
    180. 180
  180. Steensberg, A., Fischer, C. P., Keller, C., Moller, K., Pedersen, B. K. (2003) IL-6 enhances plasma IL-1ra, IL-10, and cortisol in humans Am. J. Physiol. Endocrinol. Metab. 285,E433-E437[Abstract/Free Full Text]
    181. 181
  181. Van der Poll, T., Coyle, S. M., Barbosa, K., Braxton, C. C., Lowry, S. F. (1996) Epinephrine inhibits tumor necrosis factor-{alpha} and potentiates interleukin 10 production during human endotoxemia J. Clin. Invest. 97,713-719[Medline]
    182. 182
  182. Steensberg, A., Toft, A. D., Schjerling, P., Halkjaer-Kristensen, J., Pedersen, B. K. (2001) Plasma interleukin-6 during strenuous exercise: role of epinephrine Am. J. Physiol. Cell Physiol. 281,C1001-C1004[Abstract/Free Full Text]
    183. 183
  183. Starkie, R., Ostrowski, S. R., Jaufrred, S., Febbraio, M., Pedersen, B. K. (2003) Exercise and IL-6 infusion inhibit endotoxin-induced TNF-{alpha} production in humans FASEB J. 17,884-886[Abstract/Free Full Text]
    184. 184
  184. Bagby, G. J., Sawaya, D. E., Crouch, L. D., Shepherd, R. E. (1994) Prior exercise suppresses the plasma tumor necrosis factor response to bacterial lipopolysaccharide J. Appl. Physiol. 77,1542-1547[Abstract/Free Full Text]
    185. 185
  185. Keller, C., Keller, P., Giralt, M., Hidalgo, J., Pedersen, B. K. (2004) Exercise normalizes overexpression of TNF-{alpha} in knockout mice Biochem. Biophys. Res. Commun. 321,179-182[CrossRef][Medline]
    186. 186
  186. Kraus, W. E., Houmard, J. A., Duscha, B. D., Knetzger, K. J., Wharton, M. B., McCartney, J. S., Bales, C. W., Henes, S., Samsa, G. P., Otvos, J. D., Kulkarni, K. R., Slentz, C. A. (2002) Effects of the amount and intensity of exercise on plasma lipoproteins N. Engl. J. Med. 347,1483-1492[Abstract/Free Full Text]
    187. 187
  187. Ebeling, P., Bourey, R., Koranyi, L., Tuominen, J. A., Groop, L. C., Henriksson, J., Mueckler, M., Sovijarvi, A., Koivisto, V. A. (1993) Mechanism of enhanced insulin sensitivity in athletes. Increased blood flow, muscle glucose transport protein (GLUT-4) concentration, and glycogen synthase activity J. Clin. Invest. 92,1623-1631
    188. 188
  188. Whelton, S. P., Chin, A., Xin, X., He, J. (2002) Effect of aerobic exercise on blood pressure: a meta-analysis of randomized, controlled trials Ann. Intern. Med. 136,493-503[Abstract/Free Full Text]
    189. 189
  189. Carey, A. L., Febbraio, M. A. (2004) Interleukin-6 and insulin sensitivity: friend or foe? Diabetologia 47,1135-1142[Medline]
    190. 190
  190. Lyngso, D., Simonsen, L., Bulow, J. (2002) Metabolic effects of interleukin-6 in human splanchnic and adipose tissue J. Physiol. 543,379-386[Abstract/Free Full Text]
    191. 191
  191. Steensberg, A., Fischer, C. P., Sacchetti, M., Keller, C., Osada, T., Schjerling, P., van Hall, G., Febbraio, M. A., Pedersen, B. K. (2003) Acute interleukin-6 administration does not impair muscle glucose uptake or whole-body glucose disposal in healthy humans J. Physiol. 548,631-638[Abstract/Free Full Text]
    192. 192
  192. Wallenius, V., Wallenius, K., Ahren, B., Rudling, M., Carlsten, H., Dickson, S. L., Ohlsson, C., Jansson, J. O. (2002) Interleukin-6-deficient mice develop mature-onset obesity Nat. Med. 8,75-79[CrossRef][Medline]
    193. 193
  193. Metzger, S., Hassin, T., Barash, V., Pappo, O., Chajek-Shaul, T. (2001) Reduced body fat and increased hepatic lipid synthesis in mice bearing interleukin-6-secreting tumor Am. J. Physiol. Endocrinol. Metab. 281,E957-E965[Abstract/Free Full Text]
    194. 194
  194. Metzger, S., Goldschmidt, N., Barash, V., Peretz, T., Drize, O., Shilyansky, J., Shiloni, E., Chajek-Shaul, T. (1997) Interleukin-6 secretion in mice is associated with reduced glucose-6-phosphatase and liver glycogen levels Am. J. Physiol. 273,E262-E267
    195. 195
  195. Cai, D., Yuan, M., Frantz, D. F., Melendez, P. A., Hansen, L., Lee, J., Shoelson, S. E. (2005) Local and systemic insulin resistance resulting from hepatic activation of IKK-ß and NF-{kappa}B Nat. Med. 11,183-190[CrossRef][Medline]
    196. 196
  196. Kim, H. J., Higashimori, T., Park, S. Y., Choi, H., Dong, J., Kim, Y. J., Noh, H. L., Cho, Y. R., Cline, G., Kim, Y. B., Kim, J. K. (2004) Differential effects of interleukin-6 and -10 on skeletal muscle and liver insulin action in vivo Diabetes 53,1060-1067[Abstract/Free Full Text]
    197. 197
  197. Klover, P. J., Zimmers, T. A., Koniaris, L. G., Mooney, R. A. (2003) Chronic exposure to interleukin-6 causes hepatic insulin resistance in mice Diabetes 52,2784-2789[Abstract/Free Full Text]
    198. 198
  198. Senn, J. J., Klover, P. J., Nowak, I. A., Mooney, R. A. (2002) Interleukin-6 induces cellular insulin resistance in hepatocytes Diabetes 51,3391-3399[Abstract/Free Full Text]
    199. 199
  199. Kanemaki, T., Kitade, H., Kaibori, M., Sakitani, K., Hiramatsu, Y., Kamiyama, Y., Ito, S., Okumura, T. (1998) Interleukin 1ß and interleukin 6, but not tumor necrosis factor {alpha}, inhibit insulin-stimulated glycogen synthesis in rat hepatocytes Hepatology 27,1296-1303[CrossRef][Medline]
    200. 200
  200. Klover, P. J., Clementi, A. H., Mooney, R. A. (2005) Interleukin-6 depletion selectively improves hepatic insulin action in obesity Endocrinology (Epub ahead of print)
    201. 201
  201. Senn, J. J., Klover, P. J., Nowak, I. A., Zimmers, T. A., Koniaris, L. G., Furlanetto, R. W., Mooney, R. A. (2003) Suppressor of cytokine signaling-3 (SOCS-3), a potential mediator of interleukin-6-dependent insulin resistance in hepatocytes J. Biol. Chem. 278,13740-13746[Abstract/Free Full Text]
    202. 202
  202. Stouthard, J. M., Oude Elferink, R. P., Sauerwein, H. P. (1996) Interleukin-6 enhances glucose transport in 3T3–L1 adipocytes Biochem. Biophys. Res. Commun. 220,241-245[CrossRef][Medline]
    203. 203
  203. Rotter, V., Nagaev, I., Smith, U. (2003) Interleukin-6 (IL-6) induces insulin resistance in 3T3–L1 adipocytes and is, like IL-8 and tumor necrosis factor-{alpha}, overexpressed in human fat cells from insulin-resistant subjects J. Biol. Chem. 278,45777-45784[Abstract/Free Full Text]
    204. 204
  204. Weigert, C., Hennige, A. M., Brodbeck, K., Haring, H. U., Schleicher, E. D. (2005) Interleukin-6 (IL-6) acts as insulin sensitizer on glycogen synthesis in human skeletal muscle cells by phosphorylation of Ser-473 of Akt Am. J. Physiol. Endocrinol. Metab. (Epub ahead of print)
    205. 205
  205. Castell, J. V., Geiger, T., Gross, V., Andus, T., Walter, E., Hirano, T., Kishimoto, T., Heinrich, P. C. (1988) Plasma clearance, organ distribution and target cells of interleukin-6/hepatocyte-stimulating factor in the rat Eur. J. Biochem. 177,357-361[Medline]
    206. 206
  206. Christiansen, L., Bathum, L., Andersen-Ranberg, K., Jeune, B., Christensen, K. (2004) Modest implication of interleukin-6 promoter polymorphisms in longevity Mech. Ageing Dev. 125,391-395[CrossRef][Medline]
    207. 207
  207. Fishman, D., Faulds, G., Jeffery, R., Mohamed-Ali, V., Yudkin, J. S., Humphries, S., Woo, P. (1998) The effect of novel polymorphisms in the interleukin-6 (IL-6) gene on IL-6 transcription and plasma IL-6 levels, and an association with systemic-onset juvenile chronic arthritis J. Clin. Invest. 102,1369-1376[Medline]
    208. 208
  208. Humphries, S. E., Luong, L. A., Ogg, M. S., Hawe, E., Miller, G. J. (2001) The interleukin-6 –174 G/C promoter polymorphism is associated with risk of coronary heart disease and systolic blood pressure in healthy men Eur. Heart J. 22,2243-2252[Abstract/Free Full Text]
    209. 209
  209. Jones, K. G., Brull, D. J., Brown, L. C., Sian, M., Greenhalgh, R. M., Humphries, S. E., Powell, J. T. (2001) Interleukin-6 (IL-6) and the prognosis of abdominal aortic aneurysms Circulation 103,2260-2265[Abstract/Free Full Text]
    210. 210
  210. Bruunsgaard, H., Christiansen, L., Pedersen, A. N., Schroll, M., Jorgensen, T., Pedersen, B. K. (2004) The IL-6 –174G>C polymorphism is associated with cardiovascular diseases and mortality in 80-year-old humans Exp. Gerontol. 39,255-261[CrossRef][Medline]
    211. 211
  211. Chapman, C. M., Beilby, J. P., Humphries, S. E., Palmer, L. J., Thompson, P. L., Hung, J. (2003) Association of an allelic variant of interleukin-6 with subclinical carotid atherosclerosis in an Australian community population Eur. Heart J. 24,1494-1499[Abstract/Free Full Text]
    212. 212
  212. Hurme, M., Lehtimaki, T., Jylha, M., Karhunen, P. J., Hervonen, A. (2005) Interleukin-6 –174G/C polymorphism and longevity: a follow-up study Mech. Ageing Dev. 126,417-418[CrossRef][Medline]
    213. 213
  213. Brull, D. J., Leeson, C. P., Montgomery, H. E., Mullen, M., DeDivitiis, M., Humphries, S. E., Deanfield, J. E. (2002) The effect of the interleukin-6 –174G > C promoter gene polymorphism on endothelial function in healthy volunteers Eur. J. Clin. Invest. 32,153-157[CrossRef][Medline]
    214. 214
  214. Jenny, N. S., Tracy, R. P., Ogg, M. S., Luong, le A., Kuller, L. H., Arnold, A. M., Sharrett, A. R., Humphries, S. E. (2002) In the elderly, interleukin-6 plasma levels and the –174G>C polymorphism are associated with the development of cardiovascular disease Arterioscler. Thromb. Vasc. Biol. 22,2066-2071[Abstract/Free Full Text]
    215. 215
  215. Ortlepp, J. R., Metrikat, J., Vesper, K., Mevissen, V., Schmitz, F., Albrecht, M., Maya-Pelzer, P., Hanrath, P., Weber, C., Zerres, K., Hoffmann, R. (2003) The interleukin-6 promoter polymorphism is associated with elevated leukocyte, lymphocyte, and monocyte counts and reduced physical fitness in young healthy smokers J. Mol. Med. 81,578-584[CrossRef][Medline]
    216. 216
  216. Rea, I. M., Ross, O. A., Armstrong, M., McNerlan, S., Alexander, D. H., Curran, M. D., Middleton, D. (2003) Interleukin-6-gene C/G 174 polymorphism in nonagenarian and octogenarian subjects in the BELFAST study. Reciprocal effects on IL-6, soluble IL-6 receptor and for IL-10 in serum and monocyte supernatants Mech. Ageing Dev. 124,555-561[CrossRef][Medline]
    217. 217
  217. Vickers, M. A., Green, F. R., Terry, C., Mayosi, B. M., Julier, C., Lathrop, M., Ratcliffe, P. J., Watkins, H. C., Keavney, B. (2002) Genotype at a promoter polymorphism of the interleukin-6 gene is associated with baseline levels of plasma C-reactive protein Cardiovasc. Res. 53,1029-1034[Abstract/Free Full Text]
    218. 218
  218. Olivieri, F., Bonafe, M., Cavallone, L., Giovagnetti, S., Marchegiani, F., Cardelli, M., Mugianesi, E., Giampieri, C., Moresi, R., Stecconi, R., Lisa, R., Franceschi, C. (2002) The –174 C/G locus affects in vitro/in vivo IL-6 production during aging Exp.Gerontol. 37,309-314
    219. 219
  219. Bonafe, M., Olivieri, F., Cavallone, L., Giovagnetti, S., Mayegiani, F., Cardelli, M., Pieri, C., Marra, M., Antonicelli, R., Lisa, R., Rizzo, M. R., Paolisso, G., Monti, D., Franceschi, C. (2001) A gender-dependent genetic predisposition to produce high levels of IL-6 is detrimental for longevity Eur. J. Immunol. 31,2357-2361[CrossRef][Medline]
    220. 220
  220. Nauck, M., Winkelmann, B. R., Hoffmann, M. M., Bohm, B. O., Wieland, H., Marz, W. (2002) The interleukin-6 G(–174)C promoter polymorphism in the LURIC cohort: no association with plasma interleukin-6, coronary artery disease, and myocardial infarction J. Mol. Med. 80,507-513[CrossRef][Medline]
    221. 221
  221. Basso, F., Lowe, G. D., Rumley, A., McMahon, A. D., Humphries, S. E. (2002) Interleukin-6 –174G>C polymorphism and risk of coronary heart disease in West of Scotland coronary prevention study (WOSCOPS) Arterioscler. Thromb. Vasc. Biol. 22,599-604[Abstract/Free Full Text]
    222. 222
  222. Kilpinen, S., Hulkkonen, J., Wang, X. Y., Hurme, M. (2001) The promoter polymorphism of the interleukin-6 gene regulates interleukin-6 production in neonates but not in adults Eur. Cytokine Netw. 12,62-68[Medline]
    223. 223
  223. Ershler, W. B. (2003) Biological interactions of aging and anemia: a focus on cytokines J. Am. Geriatr. Soc. 51,S18-S21[CrossRef][Medline]
    224. 224
  224. Nemeth, E., Rivera, S., Gabayan, V., Keller, C., Taudorf, S., Pedersen, B. K., Ganz, T. (2004) IL-6 mediates hypoferremia of inflammation by inducing the synthesis of the iron regulatory hormone hepcidin J. Clin. Invest. 113,1271-1276[CrossRef][Medline]
    225. 225
  225. Stouthard, J. M., Levi, M., Hack, C. E., Veenhof, C. H., Romijn, H. A., Sauerwein, H. P., Van der Poll, T. (1996) Interleukin-6 stimulates coagulation, not fibrinolysis, in humans Thromb. Haemost. 76,738-742[Medline]
    226. 226
  226. Kerr, R., Stirling, D., Ludlam, C. A. (2001) Interleukin 6 and haemostasis Br. J. Haematol. 115,3-12[CrossRef][Medline]
    227. 227
  227. Cordano, P., Lake, A., Shield, L., Taylor, G. M., Alexander, F. E., Taylor, P. R., White, J., Jarrett, R. F. (2005) Effect of IL-6 promoter polymorphism on incidence and outcome in Hodgkin’s lymphoma Br. J. Haematol. 128,493-495[CrossRef][Medline]
    228. 228
  228. Cozen, W., Gill, P. S., Ingles, S. A., Masood, R., Martinez-Maza, O., Cockburn, M. G., Gauderman, W. J., Pike, M. C., Bernstein, L., Nathwani, B. N., Salam, M. T., Danley, K. L., Wang, W., Gage, J., Gundell-Miller, S., Mack, T. M. (2004) IL-6 levels and genotype are associated with risk of young adult Hodgkin lymphoma Blood 103,3216-3221[Abstract/Free Full Text]



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