Showing papers by "Bente Klarlund Pedersen published in 2005"
TL;DR: It is suggested that myokines may be involved in mediating the health-beneficial effects of exercise and that these in particular are involved in the protection against chronic diseases associated with low-grade inflammation such as diabetes and cardiovascular diseases.
Abstract: Regular exercise offers protection against all-cause mortality, primarily by protection against cardiovascular disease and Type 2 diabetes mellitus. The latter disorders have been associated with chronic low-grade systemic inflammation reflected by a two- to threefold elevated level of several cytokines. Adipose tissue contributes to the production of TNF-alpha, which is reflected by elevated levels of soluble TNF-alpha receptors, IL-6, IL-1 receptor antagonist, and C-reactive protein. We suggest that TNF-alpha rather than IL-6 is the driver behind insulin resistance and dyslipidemia and that IL-6 is a marker of the metabolic syndrome, rather than a cause. During exercise, IL-6 is produced by muscle fibers via a TNF-independent pathway. IL-6 stimulates the appearance in the circulation of other anti-inflammatory cytokines such as IL-1ra and IL-10 and inhibits the production of the proinflammatory cytokine TNF-alpha. In addition, IL-6 enhances lipid turnover, stimulating lipolysis as well as fat oxidation. We suggest that regular exercise induces suppression of TNF-alpha and thereby offers protection against TNF-alpha-induced insulin resistance. Recently, IL-6 was introduced as the first myokine, defined as a cytokine that is produced and released by contracting skeletal muscle fibers, exerting its effects in other organs of the body. Here we suggest that myokines may be involved in mediating the health-beneficial effects of exercise and that these in particular are involved in the protection against chronic diseases associated with low-grade inflammation such as diabetes and cardiovascular diseases.
2,659 citations
TL;DR: It is demonstrated that TNF-alpha infusion in healthy humans induces insulin resistance in skeletal muscle, without effect on endogenous glucose production, as estimated by a combined euglycemic insulin clamp and stable isotope tracer method.
Abstract: Most lifestyle-related chronic diseases are characterized by low-grade systemic inflammation and insulin resistance. Excessive tumor necrosis factor-alpha (TNF-alpha) concentrations have been implicated in the development of insulin resistance, but direct evidence in humans is lacking. Here, we demonstrate that TNF-alpha infusion in healthy humans induces insulin resistance in skeletal muscle, without effect on endogenous glucose production, as estimated by a combined euglycemic insulin clamp and stable isotope tracer method. TNF-alpha directly impairs glucose uptake and metabolism by altering insulin signal transduction. TNF-alpha infusion increases phosphorylation of p70 S6 kinase, extracellular signal-regulated kinase-1/2, and c-Jun NH(2)-terminal kinase, concomitant with increased serine and reduced tyrosine phosphorylation of insulin receptor substrate-1. These signaling effects are associated with impaired phosphorylation of Akt substrate 160, the most proximal step identified in the canonical insulin signaling cascade regulating GLUT4 translocation and glucose uptake. Thus, excessive concentrations of TNF-alpha negatively regulate insulin signaling and whole-body glucose uptake in humans. Our results provide a molecular link between low-grade systemic inflammation and the metabolic syndrome.
584 citations
TL;DR: IL-6 is the first identified “myokine” released from muscle that can now be termed an endocrine organ.
Abstract: 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.
387 citations
TL;DR: IL-6 seems to be activating lipolysis independently of elevations in GH and/or cortisol and appears to be a potent catalyst for fat oxidation in muscle cells.
Abstract: To determine whether IL-6 increases lipolysis and fat oxidation in patients with type 2 diabetes and/or whether it exerts this effect independently of changes to the hormonal milieu, patients with ...
276 citations
TL;DR: In conclusion, the present study suggests that training twice every second day may be superior to daily training.
Abstract: Low muscle glycogen content has been demonstrated to enhance transcription of a number of genes involved in training adaptation. These results made us speculate that training at a low muscle glycog...
272 citations
TL;DR: It is suggested that the term "myokines" should be used exclusively to describe cytokines or other peptides, which are produced and released by muscle fibers per se, and may represent the link from working muscle to other organs such as the adipose tissue, the liver, and the vascular compartments.
Abstract: Accumulating evidence exists that regular exercise offers protection against chronic disorders such as cardiovascular diseases, type 2 diabetes, dementia, and depression. Although acute and chronic exercise has numerous consequences, it is still discussed how contracting skeletal muscles mediate metabolic and physiological effects of benefits on health. For years the search for the stimulus that initiates and maintains the change of excitability or sensibility of the regulating centers in exercise has been progressing. For lack of more precise knowledge, it has been called the 'work stimulus,' 'the work factor' or 'the exercise factor.' In other terms, the big challenge for muscle and exercise physiologists has been to determine how muscles signal to central and peripheral organs. Recently, we identified that muscle fibers produce and release the cytokine IL-6 into the circulation during exercise. We further proposed that IL-6 and other cytokines, which are produced and released by skeletal muscles, exerting their effects in other organs of the body, should be named 'myokines.' In line with that adipokines have been suggested as a term, which is restricted to cover cytokines and other peptides which are produced and secreted by adipocytes, we suggest that the term "myokines" should be used exclusively to describe cytokines or other peptides, which are produced and released by muscle fibers per se. Myokines may represent the link from working muscle to other organs such as the adipose tissue, the liver, and the vascular compartments. Here, we review the literature on muscle- and brain-derived IL-6. We further suggest that myokines may also provide an explanation as to how regular muscle activity influences mood, performance, and cognitive function.
203 citations
TL;DR: A negative association between circulating IL-6 and memory functions during very low-dose endotoxemia independently of physical stress symptoms, and the hypothalamo-pituitary-adrenal axis is demonstrated.
Abstract: Epidemiological data demonstrate an association between systemic low-grade inflammation defined as 2- to 3-fold increases in circulating inflammatory mediators and age-related decline in cognitive function. However, it is not known whether small elevations of circulating cytokine levels cause direct effects on human neuropsychological functions. We investigated changes in emotional, cognitive, and inflammatory parameters in an experimental in vivo model of low-grade inflammation. In a double-blind crossover study, 12 healthy young males completed neuropsychological tests before as well as 1.5, 6, and 24 h after an intravenous injection of Escherichia coli endotoxin (0.2 ng/kg) or saline in two experimental sessions. Endotoxin administration had no effect on body temperature, cortisol levels, blood pressure or heart rate, but circulating levels of tumor necrosis factor (TNF) and interleukin (IL)-6 increased 2- and 7-fold, respectively, reaching peak values at 3 h, whereas soluble TNF-receptors and IL-1 receptor antagonist peaked at 4.5 h. The neutrophil count increased and the lymphocyte count declined. In this model, low-dose endotoxemia did not affect cognitive performance significantly but declarative memory performance was inversely correlated with cytokine increases. In conclusion, our findings demonstrate a negative association between circulating IL-6 and memory functions during very low-dose endotoxemia independently of physical stress symptoms, and the hypothalamo-pituitary-adrenal axis.
183 citations
TL;DR: The present study demonstrated that the IL- 6R gene expression levels in skeletal muscle are increased in response to acute exercise, a response that is very well conserved, being affected by neither training status nor intramuscular glycogen levels, as opposed to IL-6.
Abstract: The cytokine interleukin-6 (IL-6) exerts it actions via the IL-6 receptor (IL-6R) in conjunction with the ubiquitously expressed gp130 receptor. IL-6 is tightly regulated in response to exercise, being affected by factors such as exercise intensity and duration, as well as energy availability. Although the IL-6 response to exercise has been extensively studied, little is known about the regulation of the IL-6R response. In the present study, we aimed to investigate the effect of exercise, training, and glycogen availability, factors known to affect IL-6, on the regulation of gene expression of the IL-6R in human skeletal muscle. Human subjects performed either 10 wk of training with an acute exercise bout before and after the training period, or a low-glycogen vs. normal-glycogen acute exercise trial. The IL-6R mRNA response was evaluated in both trials. In response to acute exercise, an increase in IL-6R mRNA levels was observed. Neither training nor intramuscular glycogen levels had an effect on the IL-6R mRNA response to exercise. However, after 10 wk of training, the skeletal muscle expressed a higher mRNA level of IL-6R compared with before training. The present study demonstrated that the IL-6R gene expression levels in skeletal muscle are increased in response to acute exercise, a response that is very well conserved, being affected by neither training status nor intramuscular glycogen levels, as opposed to IL-6. However, after the training period, IL-6R mRNA production was increased in skeletal muscle, suggesting a sensitization of skeletal muscle to IL-6 at rest.
169 citations
Journal Article•
TL;DR: The specificity of cytokine expression in different muscle fiber types in healthy young males suggests that cytokines may play specific regulatory roles in normal physiology.
Abstract: Skeletal muscle is now recognized as an endocrine organ with the capacity to produce signal peptides in response to muscle contractions. Here we demonstrate that resting healthy human muscles express cytokines in a fiber type specific manner. Human muscle biopsies from seven healthy young males were obtained from m. triceps, m. quadriceps vastus lateralis and m. soleus. Type I fibers contributed (mean +/- SE) 24.0 +/- 2.5% in triceps of total fibers, 51.3 +/- 2.4% in vastus and 84.9 +/- 22% in soleus. As expected, differences in the fiber type composition were accompanied by marked differences between the three muscles with regard to MHC I and MHC IIa mRNA expression. Immunohistochemistry demonstrated that tumor necrosis factor (TNF)-alpha and interleukin (IL)-18 were solely expressed by type II fibers, whereas the expression of IL-6 was more prominent in type I compared to type II fibers. The fiber type specificity was found in triceps, vastus and soleus indicating that the level of daily muscle activity did not influence basal cytokine expression. The specificity of cytokine expression in different muscle fiber types in healthy young males suggests that cytokines may play specific regulatory roles in normal physiology.
142 citations
TL;DR: In this article, a small transient net release of IL-8 from working muscle was found at 1.5 h of knee-extensor exercise, and the peak occurred 3-6 h postexercise.
Abstract: Skeletal muscle has been recognized as an endocrine organ, and muscle cell cultures express several cytokines with potential hormonal effects. Interleukin-8 (IL-8), a chemokine, which induces angiogenesis, is expressed in working muscles; however, the cell source of origin has not been identified. We aimed to elucidate if IL-8 protein is: (1) expressed in contracting muscle fibres and (2) whether there is a release of IL-8 from exercising muscle. Seventeen healthy male volunteers were included in two independent protocols: 3 h of ergometer bicycle exercise at 60% of VO2,max (n = 6) or rest (n = 5), and 3 h of two-legged knee-extensor exercise at 60% of maximal workload (n = 6). Repetitive muscle biopsy samples were obtained from the vastus lateralis in all experiments. A marked increase in IL-8 mRNA was found in muscle biopsy samples obtained after exercise. A marked IL-8 protein expression was demonstrated within the cytoplasm of muscle fibres in biopsy samples obtained in the recovery phase following 3 h of bicycle exercise, and the peak occurred 3-6 h postexercise. A small transient net release of IL-8 from working muscle was found at 1.5 h of knee-extensor exercise. However, the small release of IL-8 from muscle did not result in an increase in the systemic plasma concentration of IL-8, suggesting that muscle-derived IL-8 may play a local role, e.g. in angiogenesis.
124 citations
TL;DR: The results show that plasma IL-18 was associated with HOMA-IR independent of obesity and type 2 diabetes, and neither IL-6, TNF-alpha, sTNFR2, nor CRP was associatedwith HOMa-IR in CON when adjusting for confounders.
TL;DR: Exercise increases IL‐6 receptor production in human skeletal muscle, and this effect is most prominent 6 h after the end of the exercise bout, suggesting a postexercise‐sensitizing mechanism to IL-6 when plasma IL‐ 6 is concomitantly low.
Abstract: Contracting muscle fibers produce and release IL-6, and plasma levels of this cytokine are markedly elevated in response to physical exercise. We recently showed autocrine regulation of IL-6 in human skeletal muscle in vivo and hypothesized that this may involve up-regulation of the IL-6 receptor. Therefore, we investigated IL-6 receptor regulation in response to exercise and IL-6 infusion in humans. Furthermore, using IL-6-deficient mice, we investigated the role of IL-6 in the IL-6 receptor response to exercise. Human skeletal muscle biopsies were obtained in relation to: 3 h of bicycle exercise and rest (n=6+5), or recombinant human IL-6 infusion (rhIL-6) or saline infusion (n=6+6). We further obtained skeletal muscle samples from IL-6 knockout (KO) mice and wild-type C57/BL-6 mice in response to a 1-h bout of exercise. In exercising human skeletal muscle, IL-6 receptor mRNA increased sixfold with a peak at 6 h postexercise. Detection of the IL-6 receptor protein by immunohistochemistry revealed a pronounced staining following exercise that was primarily located at the cell membrane of the muscle fibers, whereas muscle gp130 expression and plasma levels of soluble IL-6 receptor were unaffected. Infusion of rhIL-6 to humans had no effect on the mRNA level of the IL-6 receptor, whereas there was an increase at the protein level. IL-6 receptor mRNA increased similarly in muscle of both IL-6 KO mice and wild-type mice in response to exercise. In conclusion, exercise increases IL-6 receptor production in human skeletal muscle. This effect is most prominent 6 h after the end of the exercise bout, suggesting a postexercise-sensitizing mechanism to IL-6 when plasma IL-6 is concomitantly low. Exercise-induced increases in IL-6 receptor mRNA most likely occurs via an IL-6 independent mechanism as shown in IL-6 KO mice and the human rhIL-6 infusion study, whereas IL-6 receptor protein levels are responsive to elevated plasma IL-6 levels.
TL;DR: If the plasma concentration of suPAR reflects the extent of parasite-induced immune activation, this may explain why a high concentration ofsuPAR is associated with a poor clinical outcome in patients with malaria.
Abstract: BACKGROUND Blood concentrations of soluble urokinase-type plasminogen activator receptor (suPAR) are increased in conditions with immune activation, and high concentrations of suPAR often predict a poor clinical outcome. This study explored the hypothesis that high plasma concentrations of suPAR are associated with disease severity in malaria. METHODS At admission to the hospital, plasma concentrations of suPAR were measured by ELISA in samples from 645 African children with clinical symptoms of malaria: 478 had malaria, and 167 had a blood film negative for Plasmodium parasites. Fourteen healthy children were included for comparison. RESULTS Plasma concentrations of suPAR were higher in patients with malaria (median, 7.90 ng/mL [interquartile range [IQR], 6.56-9.15 ng/mL]), compared with those in plasmodium-negative patients (median, 5.59 ng/mL [IQR, 4.54-8.16 ng/mL]; P < .001) and those in healthy children (3.94 ng/mL [IQR, 3.46-4.82 ng/mL]; P < .001). The highest concentrations were found in patients with malaria who died (P = .008) or had complicated malaria (P < .001). In univariate logistic regression analysis, a 1 ng/mL increase in plasma concentration of suPAR was associated with increased risk of mortality (odds ratio, 1.42 [95% confidence interval, 1.09-1.86]; P = .009). In multivariate linear regression analysis, lower platelet count, lower hemoglobin level, and higher neutrophil count were independently associated with a higher plasma concentration of suPAR. CONCLUSIONS If the plasma concentration of suPAR reflects the extent of parasite-induced immune activation, this may explain why a high concentration of suPAR is associated with a poor clinical outcome in patients with malaria.
TL;DR: It is indicated that low-level viremia and proviral DNA are intimately associated with the immunological and virological equilibrium in patients receiving HAART.
Abstract: Background. Immunological and virological consequences of low-level viremia in human immunodeficiency virus (HIV) type 1-infected patients receiving highly active antiretroviral therapy (HAART) remain to be determined.Methods. For 24 months, 101 HAART-treated, HIV-1-infected patients with HIV RNA levels ⩽200 copies/mL were followed prospectively: HIV RNA level and CD4 and CD8 cell counts were investigated every 3 months, and proviral DNA and T cell subsets were investigated every 6 months.Results. During follow-up, 33 patients had HIV RNA levels ⩽20 copies/mL at all visits (uVL patients), whereas 68 patients had HIV RNA levels >20 copies/mL at ⩾1 visit (dVL patients) (median increase, 81 copies/mL [interquartile range, 37–480 copies/mL]). dVL patients had higher concentrations of CD8 cells, activated and memory T cells, and proviral DNA, compared with uVL patients (P < .05). A higher HIV RNA level was independently associated with reduced CD4 gain (P < .001). A higher HIV RNA level also was associated with increases in activated CD8 + CD38 + and CD8 + HLA-DR + cells (P < .05), and a higher level of activated CD8 + CD38 + cells was independently associated with reduced CD4 gain (P < .05). A higher proviral DNA level was associated with increases in CD4 + CD45RA − CD28 − effector cells and reductions in naive CD4 + CD45RA + CD62L + and CD8 + CD45RA + CD62L + cells (P < .05). Higher levels of activated CD4 + HLA-DR + and early differentiated CD4 + CD45RA − CD28 + cells predicted increased risk of subsequent detectable viremia in patients with undetectable HIV RNA (P < .05).Conclusion. These findings indicate that low-level viremia and proviral DNA are intimately associated with the immunological and virological equilibrium in patients receiving HAART.
TL;DR: Plasma levels of different suPAR forms are increased and associated with immune activation in HIV patients, and su PAR(I-III) and suPAR(II- III) are independent predictors of mortality in these patients.
Abstract: Background: High blood levels of soluble urokinase receptor (suPAR) measured by enzyme-linked immunoassay (ELISA) (bulk measurement of 3-domain and 2-domain suPAR [suPAR(I-III), suPAR(II-III)], and suPAR(I-III) ligand complexes) strongly predict mortality in HIV-1-infected patients. This study investigated plasma levels of suPAR(I-III), suPAR(II-III), and 1-domain suPAR [suPAR(I)] and their predictive value for survival in HIV patients. Methods: Plasma suPAR was measured by ELISA and 3 different time-resolved fluorescence immunoassays detecting suPAR(I-III), suPAR(I-III) plus suPAR(II-III), and suPAR(I) in 99 HIV patients and 59 healthy individuals. Results: Plasma suPAR(I-III), suPAR(II-III), and suPAR(I) were increased in HIV patients and increased with HIV disease progression (P < 0.001 for all). In multivariate linear regression analysis, soluble immune activation markers and hemoglobin were independent predictors of plasma suPAR in HIV patients, whereas the neutrophil concentration was the only independent predictor of plasma suPAR in controls. In univariate Cox analysis, higher levels of suPAR(I-III), suPAR(II-III), and suPAR(I) predicted increased mortality risk (P < 0.001 for all). In multivariate Cox analysis adjusting for CD4 + count, HIV RNA, β 2 -microglobulin, hemoglobin and clinical stage, higher levels of suPAR(I-III) and suPAR(II-III) were independent predictors of increased mortality risk (P < 0.05 for both), whereas suPAR(I) was not. Conclusions: Plasma levels of different suPAR forms are increased and associated with immune activation in HIV patients, and suPAR(I-III) and suPAR(II-III) are independent predictors of mortality in these patients.
TL;DR: The finding that plasma YKL‐40 increased after endotoxin injection compared with saline (P < 0·001) suggests that YKl‐40 has a functional role in infections.
Abstract: YKL-40 is secreted by macrophages and neutrophils and patients with bacterial infections have elevated circulating YKL-40. The aim was to evaluate changes in plasma YKL-40 (determined by enzyme-linked immunosorbent assay (ELISA) at 0, 2, 4, 8, 24 and 32 h) in eight healthy volunteers after injection with Esherichia coli endotoxin or saline. Plasma YKL-40 increased after endotoxin injection from 31 microg/l (range 19-39 microg/l) to a maximum of 159 microg/l (61-552 microg/l, P < 0.01) at 24 h. The finding that plasma YKL-40 increased after endotoxin injection compared with saline (P < 0.001) suggests that YKL-40 has a functional role in infections.
TL;DR: Both acute exercise and epinephrine infusion decreased plasma leptin to a similar extent, whereas there was no effect with rhIL-6 infusion, suggesting a posttranscriptional regulatory mechanism of leptin involving substrate availability.
Abstract: 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 be 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 rhIL-6 infusion. In conclusion, both acute exercise and epinephrine infusion decreased plasma leptin to a similar extent, whereas there 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.
TL;DR: This work investigated the regulatory effects of TSPs on the activity of PAI-1 in adipose tissue and confirmed its role in the development of the metabolic syndrome.
Abstract: Plasminogen activator inhibitor-1 (PAI-1) is produced by adipose tissue, and elevated PAI-1 levels in plasma are a risk factor in the metabolic syndrome. We investigated the regulatory effects of T...
TL;DR: Exercise induces free oxygen radicals that cause oxidative stress, and metallothioneins (MTs) are increased in states of oxidative stress and possess anti‐apoptotic effects, which may represent a mechanism whereby contracting muscle fibres are protected against cellular stress and injury.
Abstract: Exercise induces free oxygen radicals that cause oxidative stress, and metallothioneins (MTs) are increased in states of oxidative stress and possess anti-apoptotic effects. We therefore studied expression of the antioxidant factors metallothionein I and II (MT-I + II) in muscle biopsies obtained in response to 3 h of bicycle exercise performed by healthy men and in resting controls. Both MT-I + II proteins and MT-II mRNA expression increased significantly in both type I and II muscle fibres after exercise. Moreover, 24 h after exercise the levels of MT-II mRNA and MT-I + II proteins were still highly increased and the MT-II mRNA expression reached a 15-fold increase. As expected, immunohistochemical detection of malondialdehyde (MDA) and nitrotyrosine (NITT) showed that formation of free radicals and oxidative stress were clearly increased in exercising muscle peaking shortly after the end of exercise in both type I and II muscle fibres. This is the first report demonstrating that MT-I + II are significantly induced in human skeletal muscle fibres following exercise. As MT-I + II are antioxidant factors that protect various tissues during pathological conditions, the MT-I + II increases post exercise may represent a mechanism whereby contracting muscle fibres are protected against cellular stress and injury.
TL;DR: Patients with pneumococcal meningitis and sepsis exhibit a cerebral output of tumor necrosis factor-α and interleukin-6, which may contribute to elevating the plasma levels of these cytokines.
Abstract: Objective:Patients with acute bacterial meningitis frequently develop sepsis, the hallmark of which is increased plasma cytokine levels. However, it is unknown whether the brain contributes to the intravascular accumulation of cytokines in meningitis. We measured the cerebral output of cytokines to
TL;DR: The finding that proviral‐DNA and sTNFrII were associated negatively with the concentration of 2B4+ NK cells suggests that immune activation in HIV‐1 infected patients receiving HAART influences the target cell recognition by NK cells.
Abstract: Human immunodeficiency virus (HIV)-1 infection influences natural killer (NK) cell expression of inhibitory NK receptors and activating natural cytotoxicity receptors. It is unknown whether expression of the co-stimulatory NK cell receptor 2B4 (CD244) on NK cells and CD3+ CD8+ cells are affected by highly active antiretroviral therapy (HAART), low-level viraemia, proviral-DNA or immune activation in HIV-1 infected patients. A total of 101 HAART-treated HIV-1 infected patients with < or = 200 HIV-RNA copies/ml were followed prospectively for 24 months. HIV-RNA was investigated 3-monthly and 2B4 expression on CD3- CD16+ NK cells and CD3+ CD8+ cells, proviral-DNA and plasma soluble tumour necrosis factor receptor (sTNFr)-II were investigated 6-monthly. For comparison, 2B4 expression was investigated in 20 healthy individuals. The concentration of 2B4+ NK cells was initially reduced in HIV-1 infected patients (P < 0.001) but increased to a normal level during the 24 months' follow-up. The concentration of CD3+ CD8+ 2B4+ cells in HIV-1 infected patients was normal and did not change during follow-up. The relative fluorescence intensity (RFI) of 2B4 increased on both NK cells and CD3+ CD8+ cells during follow-up (both P < 0.001). Higher levels of proviral-DNA carrying cells and plasma sTNFrII were associated with reductions in the concentration of 2B4+ NK cells (all P < 0.05). HIV-RNA had no effect on 2B4 expression on NK cells or CD3+ CD8+ cells. These findings demonstrate that the concentration of 2B4+ NK cells normalizes during long-term HAART in HIV-1 infected patients. The finding that proviral-DNA and sTNFrII were associated negatively with the concentration of 2B4+ NK cells suggests that immune activation in HIV-1 infected patients receiving HAART influences the target cell recognition by NK cells.
TL;DR: The data show that a low dose of rhIL-6, administered during low-intensity exercise without altering the hormonal milieu, does not alter fatty acid metabolism, and suggest that the increase in fatty acid utilization seen during exercise at moderate compared with low intensity is not mediated via alterations in plasma IL-6.
Abstract: The present study examined the role of the cytokine IL-6 in the regulation of fatty acid metabolism during exercise in humans. Six well-trained males completed three trials of 120 min of cycle ergo...
TL;DR: The inhibitory effect of IL‐6 on endotoxin‐mediated uPAR‐release in vitro suggests that IL‐ 6 has anti‐inflammatory effects on endotoxaemia‐mediated inflammation.
Abstract: Leucocyte expression of the urokinase receptor [urokinase-type plasminogen activator receptor (uPAR)] is regulated by inflammatory mediators. This study investigated the in vivo effect of endotoxin, interleukin (IL)-6 and tumour necrosis factor (TNF)-alpha on uPAR-release in vivo and in vitro in humans. Healthy subjects received intravenous endotoxin injection [high-dose, 2 ng/kg (n=8) and low-dose, 0.06 ng/kg (n=7)], coadministration of 0.06 ng/kg endotoxin and 3 h recombinant human (rh)IL-6 infusion (n=7) or 3 h infusion of rhIL-6 (n=6), rhTNF-alpha (n=6) or NaCl (n=5). Soluble uPAR (suPAR) was measured by enzyme-linked immunosorbent assay in plasma and supernatants from unstimulated and phytohaemagglutinin and lipopolysaccharide-stimulated peripheral blood mononuclear cell (PBMC) cultures incubated for 24 h. The spontaneous and stimulated uPAR-release from PBMC cultures was enhanced 5 h after low-dose endotoxin (both P <0.05), but coadministration of rhIL-6 during low-dose endotoxaemia abolished this enhanced uPAR release. High-dose endotoxin increased plasma suPAR levels (P <0.001) whereas low-dose endotoxin, rhIL-6 or TNF-alpha did not influence uPAR release in vivo to such degree that a systemic effect on the plasma suPAR level was detectable. Even subclinical doses of endotoxin in vivo enhance the capacity of PBMC to release uPAR after incubation in vitro. The inhibitory effect of IL-6 on endotoxin-mediated uPAR-release in vitro suggests that IL-6 has anti-inflammatory effects on endotoxin-mediated inflammation.
TL;DR: It is demonstrated that HIV infection affects stimulated and spontaneous uPAR release in whole‐blood cultures from HIV patients, and that perturbations in uPARrelease in whole-blood cultures may also reflect immune activation.
Abstract: The blood levels of the soluble forms of the urokinase receptor (suPAR) are increased in human immunodeficiency virus (HIV)-1-infected patients. This study investigated whether the release of urokinase-type plasminogen activator receptor (uPAR) in whole-blood cultures was affected by HIV infection. The release of different uPAR forms in whole-blood cultures incubated 24 h with or without phytohemagglutinin and lipopolysaccharide was analysed in 47 HIV patients and 19 controls. suPAR was measured by enzyme-linked immunosorbent assay (ELISA) (bulk-suPAR) and three different time-resolved fluorescence immunoassays measuring three-domain suPAR [suPAR(I-III)], three- and two-domain suPAR [suPAR(I-III) + suPAR(II-III)] and one-domain suPAR [suPAR(I)]. The uPAR release was correlated to leucocyte subpopulations and plasma levels of suPAR. The stimulated net whole-blood culture release of bulk-uPAR, uPAR(I-III), uPAR(II-III) and uPAR(I) was reduced in HIV patients (all P < 0.01), whereas the spontaneous bulk-uPAR and uPAR(I-III) release was increased in HIV patients (both P < 0.05). The stimulated uPAR release in whole-blood cultures correlated well to leucocytes and circulating suPAR levels in controls, whereas the correlation was weaker to leucocytes and nonexisting to circulating suPAR levels in HIV patients. These findings demonstrate that HIV infection affects stimulated and spontaneous uPAR release in whole-blood cultures. Given that high blood levels of suPAR in HIV patients are linked to immune activation, the perturbations in uPAR release in whole-blood cultures from HIV patients may also reflect immune activation.
TL;DR: In this article, it has been shown that IL-6 is produced locally in contracting skeletal muscles and that the net release from the muscle can account for the exercise-induced increase in arterial IL6 concentration.
Abstract: Natural immunity is influenced by exercise. Physical activity induces increased circulating levels of a number of cytokines. IL-6 more than any other cytokine is produced in large amounts in response to exercise. Recently, it has been demonstrated that IL-6 is produced locally in contracting skeletal muscles and that the net release from the muscle can account for the exercise-induced increase in arterial IL-6 concentration. IL-6 stimulates the production of a number of anti-inflammatory cytokines such as IL-1ra and IL-10 and works in a hormone-like fashion. IL-6 also stimulates cortisol production. In the recovery phase of heavy exertion, a cortisol-induced shift in leukocyte subsets is seen. Thus, dominant features in the post-exercise period are lymphopenia, neutrophilia and a marked suppressed natural killer cell activity are seen. In addition secretory IgA is inhibited.
01 Jan 2005
TL;DR: It is suggested that the term ‘‘myokines’’ should be used exclusively to describe cytokines or other peptides, which are produced and released by muscle fibers per se, and may represent the link from working muscle to other organs such as the adipose tissue, the liver, and the vascular compartments.
Abstract: Accumulating evidence exists that regular exercise offers protection against chronic disorders such as cardiovascular diseases, type 2 diabetes, dementia, and depression. Although acute and chronic exercise has numerous consequences, it is still discussed how contracting skeletal muscles mediate metabolic and physiological effects of benefits on health. For years the search for the stimulus that initiates and maintains the change of excitability or sensibility of the regulating centers in exercise has been progressing. For lack of more precise knowledge, it has been called the work stimulus,the work factor or the exercise factor. In other terms, the big challenge for muscle and exercise physiologists has been to determine how muscles signal to central and peripheral organs. Recently, we identified that muscle fibers produce and release the cytokine IL-6 into the circulation during exercise. We further proposed that IL-6 and other cytokines, which are produced and released by skeletal muscles, exerting their effects in other organs of the body, should be named myokines. In line with that adipokines have been suggested as a term, which is restricted to cover cytokines and other peptides which are produced and secreted by adipocytes, we suggest that the term ‘‘myokines’’ should be used exclusively to describe cytokines or other peptides, which are produced and released by muscle fibers per se. Myokines may represent the link from working muscle to other organs such as the adipose tissue, the liver, and the vascular compartments. Here, we review the literature on muscle- and brain-derived IL-6. We further suggest that myokines may also provide an explanation as to how regular muscle activity influences mood, performance, and cognitive function. 2005 Elsevier Inc. All rights reserved.
TL;DR: It is suggested that training twice every second day may be superior to daily training for one‐knee legged exercise training.
Abstract: Low muscle glycogen content has been demonstrated to enhance transcription of a number of genes involved in training adaptation. These results made us speculate that training at a low muscle glycogen content would enhance training adaptation. We therefore performed a study in which seven healthy untrained males performed one-knee legged exercise training at a low glycogen (Low) protocol, whereas the other leg was trained at a high glycogen (High) protocol. Both legs were trained equally regarding workload and training amount. Day one: Both legs (Low+High) were trained for 1 h followed by 2 h of rest at a fasting state, where after one leg (Low) was trained for one more hour. Day 2: Only one leg (High) trained for 1 h. Days 1 and 2 were repeated for 10 weeks. As an effect of training, the increase in maximal workload was identical for the two legs. However, time till exhaustion at 90% was markedly more increased in the Low leg compared with the High leg. Resting muscle glycogen and the activity of the mitochondrial enzyme hydroxyacyl CoA dehydrogenase (HAD) increased with training, but only significantly so in LOW, whereas citrate synthase (CS) activity increased in both low and high. There was a more pronounced increase in CS activity when Low was compared with High. In conclusion, the present study suggests that training twice every second day may be superior to daily training.