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During the past decade, skeletal muscle has been identified as a secretory organ. Accordingly, we have suggested that cytokines and other peptides that are produced, expressed and released by muscle fibres and exert either autocrine, paracrine or endocrine effects should be classified as myokines. The finding that the muscle secretome consists of several hundred secreted peptides provides a conceptual basis and a whole new paradigm for understanding how muscles communicate with other organs, such as adipose tissue, liver, pancreas, bones and brain. However, some myokines exert their effects within the muscle itself. Thus, myostatin, LIF, IL-6 and IL-7 are involved in muscle hypertrophy and myogenesis, whereas BDNF and IL-6 are involved in AMPK-mediated fat oxidation. IL-6 also appears to have systemic effects on the liver, adipose tissue and the immune system, and mediates crosstalk between intestinal L cells and pancreatic islets. Other myokines include the osteogenic factors IGF-1 and FGF-2; FSTL-1, which improves the endothelial function of the vascular system; and the PGC-1α-dependent myokine irisin, which drives brown-fat-like development. Studies in the past few years suggest the existence of yet unidentified factors, secreted from muscle cells, which may influence cancer cell growth and pancreas function. Many proteins produced by skeletal muscle are dependent upon contraction; therefore, physical inactivity probably leads to an altered myokine response, which could provide a potential mechanism for the association between sedentary behaviour and many chronic diseases.

Physical inactivity has recently been identified as a major and independent risk factor for the development of dementia and cognitive decline. In addition to the effect of exercise with regard to protection against neurodegenerative diseases, it is well-established that physical inactivity increases the risk of type 2 diabetes, cardiovascular diseases (CVD), colon cancer and postmenopausal breast cancer. These diseases constitute a network of related diseases, also called "the diseasome of physical inactivity". In this review, physical inactivity is given the central role as an independent and strong risk factor for accumulation of visceral fat and consequently the activation of a network of systemic inflammatory pathways, which promote development of neurodegeneration as well as insulin resistance, atherosclerosis, and tumour growth. The recent finding that muscles produce and release myokines provides a conceptual basis for understanding some of the molecular mechanisms underlying organ cross talk, including muscle-fat cross talk. Accumulating data suggest that contracting skeletal muscles release myokines, which may work in a hormone-like fashion, exerting specific endocrine effects on visceral fat or mediating direct anti-inflammatory effects. Other myokines work locally within the muscle via paracrine mechanisms, exerting their effects on signalling pathways involved in fat oxidation., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Purpose: Type 2 diabetes is associated with an increased risk of acquiring infectious diseases and developing sepsis. This may partly be due to immune dysfunction. We investigated the in vivo innate immune response of type 2 diabetic persons to an intravenous injection of E. coli lipopolysaccharide (LPS)., Methods: After ethics approval, informed consent and a thorough physical examination, 19 type 2 diabetic patients and 23 healthy controls were included. LPS was given as an intravenous bolus injection of 0.3 ng/kg. Physiological variables, white blood cell count, and plasma concentrations of tumour necrosis factor (TNF), interleukin-6 (IL-6), interleukin-1 receptor antagonist (IL-1ra), and the adhesion molecules E-selectin, vascular adhesion molecule (VCAM)-1, and intracellular adhesion molecule (ICAM)-1 were measured hourly for 8 h., Results: LPS injection induced a systemic inflammatory response with increases in neutrophils, temperature, heart rate and plasma concentrations of cytokines and adhesion molecules in healthy and type 2 diabetic volunteers. Type 2 diabetes was associated with less pronounced LPS-induced increases in TNF, IL-1ra, VCAM-1 and ICAM-1. There was a trend towards an attenuated upregulation of E-selectin in diabetics, even though the plasma concentration tended to be generally higher compared to healthy controls., Conclusions: Patients with type 2 diabetes exhibit an attenuated increase in plasma levels of TNF and IL-1ra, as well as an attenuated upregulation of VCAM-1 and ICAM-1 to LPS in vivo. This finding may provide a mechanistic explanation for the adverse outcome seen during infectious diseases in diabetic patients.

Systemic low-grade inflammation is consistently associated with functional status, cognitive functioning, multimorbidity, and survival in oldest olds. If inflammation is either a cause or a consequence of age-related pathology, genetic determinants of late-life survival can reside in cytokine genes polymorphisms, regulating inflammatory responses. The aim of this study was to test associations between commonly studied polymorphisms in interleukin (IL)6, IL10, IL15, and IL18, and tumor necrosis factor-alpha genes and late-life survival in a longitudinal cohort of nonagenarians: the Danish 1905 cohort. Additionally, associations were investigated between inflammatory markers and major predictors of mortality as cognitive and functional status. Modest sex-specific associations were found with survival, cognitive functioning, and handgrip strength. Evaluation of combined genotypes indicated that, in nonagenarian men, the balance of pro- and anti-inflammatory activity at IL18 and IL10 loci is protective against cognitive decline. In conclusion, in this large study with virtually complete follow-up, commonly studied polymorphisms in cytokine genes do not have a major impact on late-life survival or associated risk phenotypes.

Chronic inflammation is involved in the pathogenesis of insulin resistance, atherosclerosis, neurodegeneration, and tumour growth. Regular exercise offers protection against type 2 diabetes, cardiovascular diseases, colon cancer, breast cancer, and dementia. Evidence suggests that the protective effect of exercise may to some extent be ascribed to the antiinflammatory effect of regular exercise. Here we suggest that exercise may exert its anti-inflammatory effect via a reduction in visceral fat mass and/or by induction of an anti-inflammatory environment with each bout of exercise. According to our theory, such effects may in part be mediated via muscle-derived peptides, so-called "myokines". Contracting skeletal muscles release myokines with endocrine effects, mediating direct anti-inflammatory effects, and/or specific effects on visceral fat. Other myokines work locally within the muscle and exert their effects on signalling pathways involved in fat oxidation and glucose uptake. By mediating anti-inflammatory effects in the muscle itself, myokines may also counteract TNF-driven insulin resistance. In conclusion, exercise-induced myokines appear to be involved in mediating both systemic as well as local anti-inflammatory effects.

Type 2 diabetes, cardiovascular diseases, colon cancer, breast cancer, dementia and depression constitute a cluster of diseases, which defines 'a diseasome of physical inactivity'. Both physical inactivity and abdominal adiposity, reflecting accumulation of visceral fat mass, are associated with the occurrence of the diseases within the diseasome. Physical inactivity appears to be an independent and strong risk factor for accumulation of visceral fat, which again is a source of systemic inflammation. Chronic inflammation is involved in the pathogenesis of insulin resistance, atherosclerosis, neurodegeneration and tumour growth. Evidence suggests that the protective effect of exercise may to some extent be ascribed to the anti-inflammatory effect of regular exercise, which can be mediated via a reduction in visceral fat mass and/or by induction of an anti-inflammatory environment with each bout of exercise. The finding that muscles produce and release myokines provides a conceptual basis to understand the mechanisms whereby exercise influences metabolism and exerts anti-inflammatory effects. According to our theory, contracting skeletal muscles release myokines, which work in a hormone-like fashion, exerting specific endocrine effects on visceral fat. Other myokines work locally within the muscle via paracrine mechanisms, exerting their effects on signalling pathways involved in fat oxidation.

Physical exercise induces a network of alterations in the transcriptome and proteome of the skeletal muscle, resulting in modifications of the muscle physiology. Intriguingly, exercise also transiently induces the production of both reactive oxygen species (ROS) and some inflammatory cytokines in skeletal muscle. In fact, it seems that exercise-induced ROS are able to stimulate cytokine production from skeletal muscle. Despite the initial view that ROS were potentially cell damaging, it now seems possible that these substances have important roles in the regulation of cell signaling. Muscle-derived cytokines, so-called 'myokines', are distinguished from inflammation and instead possess important anti-inflammatory and metabolic properties. In this opinion piece, we suggest that both ROS and myokines are important players in muscle adaptation to exercise.

The concentration of plasma interleukin-6 (IL-6) increases during physical exercise, but until recently the cellular origin of this increase has been unknown. Recent work has identified that skeletal muscle is a major source of this increase and the release of IL-6 from muscle can mediate metabolic processes. IL-6 is, therefore, the first identified "myokine" released from muscle that can now be termed an endocrine organ.

Objectives: With regard to the natural history of HIV-1 infection this study investigated whether whole-blood culture cytokine production was associated with mortality in HIV-1-infected patients., Design and Methods: One hundred and seven HIV-1-infected patients stratified according to the Centers for Disease Control and Prevention criteria and 65 controls participated. The 24-h phytohaemagglutinin and lipopolysaccharide-stimulated whole-blood culture production of tumour necrosis factor (TNF)-alpha, interferon (IFN)-gamma, interleukin (IL) receptor antagonist (-ra), IL-1beta, IL-12, IL-10, IL-2 and soluble (s) IL-2 receptor (-r)alpha were studied and progression was evaluated using Kaplan-Meier method and Cox proportional-hazards models., Results: Compared with controls, asymptomatic patients had increased production of IL-1beta and IL-12 (both P< 0.05), unchanged production of TNF-alpha, IFN-gamma and IL-1ra and notably reduced production of IL-10, IL-2 and sIL2-ralpha (all P< 0.05). HIV progression led to a progressive decline in whole-blood culture production of TNF-alpha, IFN-gamma, IL-1ra, IL-1beta, IL-12, IL-10 and IL-2 (all P< 0.0001). Low production of these cytokines were all associated with increased mortality risk in the patients (log-rank test, all P < 0.01, univariate Cox, all P< 0.001). Furthermore, low production of TNF-alpha, IL-1beta, IL-12 and IL-10 independently predicted mortality after adjusting for other known prognostic variables (multivariate Cox, all P< 0.05)., Conclusions: Preserved capacity of blood cells to produce cytokines was associated with prolonged survival in HIV-1-infected patients indicating a clinical significance of impaired cytokine production in HIV-1 infection.

End‐stage renal failure is associated with persistent systemic inflammation. The aim of this study was to investigate if systemic inflammation at the time of kidney transplantation is linked to poor graft survival, major adverse cardiovascular events (MACE), and increased mortality, and if these processes are modulated by naturally occurring cytokine‐specific autoantibodies (c‐aAbs), which have been shown to regulate cytokine activity in vitro. Serum levels of cytokines, high‐sensitivity C‐reactive protein (hsCRP) and c‐aAbs specific for interleukin (IL)‐1α, tumor necrosis factor (TNF)‐α, IL‐6, and IL‐10 were measured at the time of transplantation in a retrospective cohort study of 619 kidney transplanted patients with a median follow‐up of 4.9 years (range 1.2–8.2 years). Systemic inflammation was associated with all‐cause mortality in simple and multiple Cox regression analyses. IL‐10‐specific c‐aAbs were associated with MACE after transplantation, suggesting that IL‐10 may be a protective factor. Similarly, patients with a history of MACE before transplantation had lower levels of TNF‐α‐specific c‐aAbs, hence we hypothesized that TNF may be a risk factor of MACE. These findings support that pro‐inflammatory activity before transplantation is a pathological driver of MACE and all‐cause mortality after transplantation. This information adds to pretransplantation risk estimation in renal transplant candidates. [ABSTRACT FROM AUTHOR]

Background: Exercise may improve depression in cancer patients, yet the molecular mechanism behind this protection is poorly understood. Here, we aimed to explore the link between exercise and regulation of kynurenine (Kyn) metabolism and inflammation in patients with operable gastro-esophageal junction (GEJ) cancer patients, who improved significantly in depression score with exercise training. Material and Methods: Fifty GEJ cancer patients were allocated to 12 weeks of supervised training twice weekly including interval-based aerobic exercise and resistance training, or standard care. Depression score was evaluated by HADS, and blood samples and muscle biopsies were collected for determination of Kyn metabolism and inflammation across the intervention. Results: Depression scores decreased by −1.3 points in the exercise group (p < 0.01), whereas no changes were observed in the control group. Plasma 3-hydroxykynurenine (HK), a Kyn metabolite giving rise to other neurotoxic metabolites, increased by 48% (p <0.001) in the control group, while exercise training attenuated this accumulation. The production of HK is induced by inflammation, and while we observed no differences in systemic pro-inflammatory cytokines, exercise training ameliorated the treatment-induced intramuscular inflammation. Moreover, exercise has been suggested to convert Kyn to the neuroprotective metabolite, kynurenic acid (KA), but despite marked functional and muscular exercise-mediated adaptations, we did not observe any enhancement of KA production and related enzyme expression in the muscles of GEJ cancer patients. Conclusion: Exercise training reduced symptoms of depression in patients with GEJ cancer, and this effect was associated with an exercise-dependent attenuation of the inflammation-induced conversion of Kyn to neurotoxic metabolites. [ABSTRACT FROM AUTHOR]

Skeletal muscle secretes several hundred myokines that facilitate communication from muscle to other organs, such as, adipose tissue, pancreas, liver, gut, and brain. The biological roles of myokines include effects on e.g., memory and learning, as well as glucose and lipid metabolism. The present minireview focuses on recent developments showing that exercise-induced myokines are involved in immunometabolism of importance for the control of e.g., tumor growth and chronic inflammation. In this review, immunometabolism is discussed as the non-immune related pathologies leading to an immune response and some degree of inflammation, which promotes metabolic abnormalities.

Interleukin ( IL)-6 is a cytokine with pleiotropic functions in different tissues and organs. Skeletal muscle produces and releases significant levels of IL-6 after prolonged exercise and is therefore considered as a myokine. Muscle is also an important target of the cytokine. IL-6 signaling has been associated with stimulation of hypertrophic muscle growth and myogenesis through regulation of the proliferative capacity of muscle stem cells. Additional beneficial effects of IL-6 include regulation of energy metabolism, which is related to the capacity of actively contracting muscle to synthesize and release IL-6. Paradoxically, deleterious actions for IL-6 have also been proposed, such as promotion of atrophy and muscle wasting. We review the current evidence for these apparently contradictory effects, the mechanisms involved and discuss their possible biological implications. [ABSTRACT FROM AUTHOR]

IL-6 is believed to mediate the elevation in plasma TG and VLDL lipids in patients with sepsis. Previous studies of lipoprotein density fractions do not reveal the extent to which cytokines change the immunochemically distinct TG-rich (LpB:C, LpB:C:E, LpAII:B:C:D:E) and cholesterol-rich (LpB, LpB:E) apoB-containing subclasses present in VLDL. Therefore, we have directly measured these subclasses following their isolation by sequential immunoprecipitation in seven healthy male subjects during a 3-h infusion with recombinant human (rh) IL-6. Though plasma TG and apoB-containing particle number were unchanged by IL-6, the distribution of TG-rich subclasses was significantly altered. Compared to baseline values, LpB:E ++ LpB:C:E increased significantly at 0.5 h ( p < 0.02) and were higher than saline-infused controls at 0.5 and 1 h ( p < 0.05). At 0.5 h LpAII:B:C:D:E reciprocally declined from baseline ( p < 0.01). While the pattern of change for total apoB showed an overall decline ( p < 0.05), these changes in LpB:E ++ LpB:C:E and LpAII:B:C:D:E in IL-6 subjects differed from controls ( p < 0.05; p < 0.01, respectively). These findings indicate that physiologic concentrations of IL-6 rapidly and selectively regulate the transport of apoB particles that contain apoE. Since apoE has immunomodulatory and host defense functions, these changes may be a previously unrecognized early step in the innate immune response. [ABSTRACT FROM AUTHOR]

Skeletal muscle is an endocrine organ that produces and releases myokines in response to contraction. Some myokines are likely to work in a hormone-like fashion, exerting specific endocrine effects on other organs such as the liver, the brain, and the fat. Other myokines will work locally via paracrine mechanisms, exerting, e.g., angiogenetic effects, whereas yet other myokines work via autocrine mechanisms and influence signaling pathways involved in fat oxidation and glucose uptake. The finding that muscles produce and release myokines creates a paradigm shift and opens new scientific, technological, and scholarly horizons. This finding represents a breakthrough within integrative physiology and contributes to our understanding of why regular exercise protects against a wide range of chronic diseases. Thus the myokine field provides a conceptual basis for the molecular mechanisms underlying, e.g., muscle-fat, muscle-liver, muscle-pancreas, and muscle-brain cross talk. [ABSTRACT FROM AUTHOR]

The article provides information on the research study entitled, "Muscle as an Endocrine Organ: Focus on Muscle-Derived Interleukin-6." Skeletal muscle is now considered as part of the endocrine system because it secretes and excretes myokines. The first studied myokine is the gp130 receptor cytokines interleukin-6 (IL-6). IL-6 was found out to be a myokine because its amount increase by 100 times during physical exercise. Here, the mechanisms and roles of IL-6 in the human body are discussed.

It is not clear how contracting skeletal muscles mediate the numerous and diverse metabolic and physiological effects that are beneficial for health. Researchers have searched for a muscle-contraction-induced factor – an ‘exercise factor’ – that mediates some of the exercise effects in other tissues such as the liver and adipose tissue. In our search for such a factor, we encountered the cytokine interleukin (IL)-6, which is produced by contracting muscles and released into the blood. We propose that muscle-derived IL-6 meets the criteria of an exercise factor and that such classes of cytokine should be named ‘myokines’. The discovery of contracting muscle as a cytokine-producing organ creates a new paradigm: skeletal muscle as an endocrine organ. By contracting, it stimulates the production and release of myokines that can influence metabolism in tissue and organs. Newly identified myokines and their receptors could serve as targets in the treatment of metabolic disorders and other diseases. [Copyright &y& Elsevier]

Inflammation is associated with insulin resistance, and both tumor necrosis factor (TNF)-a and interleukin (IL)-6 may affect glucose uptake. TNF induces insulin resistance, whereas the role of IL-6 is controversial. High plasma levels of IL-18 are associated with insulin resistance in epidemiological studies. We investigated the effects of TNF and IL-6 on IL-18 gene expression in skeletal muscle and adipose tissue. Nine human volunteers underwent three consecutive interventions, receiving an infusion of recombinant human (rh)IL-6, rhTNF, and saline. Insulin sensitivity was assessed by measurement of whole body glucose uptake with the stable isotope tracer method during a euglycemic hyperinsulinemic clamp (20 mUmin-1kg-1), which was initiated 1 h after the IL-6-TNF-saline infusion. Cytokine responses were measured in plasma, muscle, and fat biopsies. Plasma concentrations of TNF and IL-6 increased 10- and 38-fold, respectively, during the cytokine infusions. Whole body insulin-mediated glucose uptake was significantly reduced during TNF infusion but remained unchanged during IL-6 infusion. TNF induced IL-18 gene expression in muscle tissue, but not in adipose tissue, whereas IL-6 infusion had no effect on IL-18 gene expression in either tissue. We conclude that TNF-induced insulin resistance of whole body glucose uptake is associated with increased IL-18 gene expression in muscle tissue, indicating that TNF and IL-18 interact, and both may have important regulatory roles in the pathogenesis of insulin resistance. [ABSTRACT FROM AUTHOR]

Leptin, an adipose tissue-derived cytokine, is correlated with adipose mass as obese persons have increased levels of leptin that decrease with weight loss. Previous studies demonstrate that high-energy-expenditure exercise decreases circulating leptin levels, whereas low-energy-expenditure exercise has no effect. We aimed to test the hypothesis that acute exercise reduced leptin mRNA levels in human adipose tissue and that this effect would be ameliorated by carbohydrate supplementation. Because exercise markedly increases circulating IL-6 and epinephrine, we investigated whether the changes in leptin seen with acute exercise could he mediated by IL-6 or epinephrine infusion. Abdominal subcutaneous adipose tissue mRNA and plasma levels of leptin were measured in healthy men in response to 3-h ergometer exercise with or without carbohydrate (CHO) ingestion (n = 8) and in response to infusion with recombinant human (rh)IL-6 (n = 11) or epinephrine (n = 8) or saline. Plasma leptin declined in response to exercise (P < 0.05) compared with rest, whereas mRNA expression in adipose tissue was unaffected. The exercise-induced decrease in plasma leptin was attenuated by CHO ingestion (P < 0.001). A 3-h epinephrine infusion decreased plasma leptin (P < 0.001) to the same level seen with 3 h of exercise, whereas leptin levels were unaffected by rhlL-6 infusion. In conclusion, both acute exercise and epinephrine infusion decreased plasma leptin to a similar extent, whereas them was no effect with rhIL-6 infusion. Acute exercise solely affected leptin plasma levels, as mRNA levels were unchanged. The exercise-induced decrease in circulating leptin was counteracted by CHO ingestion, suggesting a posttranscriptional regulatory mechanism of leptin involving substrate availability. [ABSTRACT FROM AUTHOR]

The mechanisms that mediate the tightly controlled production and clearance of glucose during muscular work are unclear, and it has been suggested that an unidentified "work factor" exists that influences the contraction-induced increase in endogenous glucose production (EGP). The cytokine interleukin (IL)-6 is released from skeletal muscle during contraction. Here we show that IL-6 contributes to the contraction-induced increase in EGP. Six men performed 2 h of bicycle exercise on three separate occasions, at a relatively high intensity (HI) or at a low intensity with (LO + IL-6) or without (LO) an infusion of recombinant human IL-6 that matched the circulating concentration of IL-6 seen in HI exercise. The stable isotope 6,6 (2)H(2) glucose was infused to calculate EGP (rate of glucose appearance [R(a)]), whole-body glucose disposal (rate of glucose disappearance [R(d)]), and metabolic clearance rate (MCR) of glucose. Glucose R(a), R(d), and MCR were higher (P < 0.05) at HI than at LO. Throughout exercise at LO + IL-6, glucose R(a) and R(d) were higher (P < 0.05) than LO, even though the exercise intensity was identical. In addition, MCR was higher (P < 0.05) at LO + IL-6 than at LO at 90 min. Insulin, glucagon, epinephrine, norepinephrine, cortisol, and growth hormone were identical when comparing LO + IL-6 with LO. These data suggest that IL-6 influences glucose homeostasis during exercise. Our results provide potential new insights into factors that mediate glucose production and disposal and implicates IL-6 in the so-called "work factor." [ABSTRACT FROM AUTHOR]

Abstract: Plasma levels of YKL-40 are elevated in patients with systemic infection, inflammatory disorders and cancer. Both monocytes/macrophages, neutrophils, and cancer cells have the capacity to produce YKL-40, but the regulation during the inflammatory response is unknown. To study the possible role of interleukin-6 (IL-6) and tumor necrosis factor (TNF)-α in the regulation of YKL-40 plasma levels, we included healthy men, who received either recombinant human (rh)IL-6 (n =6), rhTNF-α (n =8) or vehicle (n =7) for 3h. The plasma levels of IL-6 and TNF-α reached ∼150 and ∼18pg/ml, respectively, during the infusions. Following the IL-6 infusion, the plasma level of YKL-40 increased from ∼30 to ∼57ng/ml (p <0.05) at 24h, and returned to normal values after 48h. The plasma level of YKL-40 did not change during TNF-α infusion or infusion of vehicle. These data demonstrate that IL-6, but not TNF-α, has a key-role in the regulation of plasma YKL-40 levels during inflammation. [Copyright &y& Elsevier]

Abstract: Elevated plasma IL-18 is present in several conditions sharing insulin-resistance as common trait, but the association with insulin-resistance per se is not established. Plasma/serum IL-6, IL-18, TNF-α, soluble TNF receptor II (sTNFR2), and C-reactive protein (CRP) were measured in 97 patients with type 2 diabetes (DM) and 84 non-diabetic controls (CON). The association with insulin-resistance—estimated using the homeostasis model assessment (HOMA-IR)—was analyzed using multivariate linear and logistic regression. Compared to CON, DM demonstrated higher plasma levels of IL-18 (P = 0.001), IL-6 (P < 0.001), sTNFR2 (P = 0.005), and CRP (P < 0.001), while TNF-α was lower (P = 0.017). Plasma IL-18 increased across HOMA-IR quartiles in both DM and CON, both with and without adjustment for confounders (all P < 0.05). In contrast, neither IL-6, TNF-α, sTNFR2, nor CRP was associated with HOMA-IR in CON when adjusting for confounders. Accordingly, 50% increase of IL-18 corresponded to a marked increase of HOMA-IR in both DM and CON (DM: 26%, P = 0.014; CON: 25%, P = 0.003) after adjustment for confounders. Our results show that plasma IL-18 was associated with HOMA-IR independent of obesity and type 2 diabetes. [Copyright &y& Elsevier]

Interleukin-6 (IL-6) is a cytokine with immuno-regulatory functions. However, contracting skeletal muscle expresses and subsequently releases IL-6 in high amounts, and recent evidence in IL-6 deficient mice suggests a role of IL-6 in metabolism. Since IL-6 mRNA levels also increase in abdominal adipose tissue in response to exercise, we wanted to examine the possible existence of a positive feedback mechanism between muscle and adipose tissue. We obtained biopsies from human skeletal muscle and abdominal subcutaneous adipose tissue in relation to either 3 h of bicycle exercise or recombinant human IL-6 infusion (rhIL-6) or saline infusion. In muscle, IL-6 mRNA increased (p<0.05) immediately after exercise, peaking at this time-point, whereas IL-6 mRNA in adipose tissue increased 1.5-h post exercise (p<0.05) displaying a different kinetic of induction. During rhIL-6 infusion, IL-6 mRNA increased 120-fold in muscle (p<0.05). In conclusion, the present study demonstrates that muscle IL-6 is regulated by an autocrine mechanism at the transcriptional level. [Copyright &y& Elsevier]