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Biomedical subjects

B K Pedersen

Publications and source records attributed to B K Pedersen.

At least 37 records · Page 2Linked to original sources
PubMed2003

Glutamine supplementation further enhances exercise-induced plasma IL-6.

Exercise stimulates the production and release of interleukin-6 (IL-6) from skeletal muscle. Glutamine is also synthesized in skeletal muscle and is involved in protein synthesis within this tissue. During exercise, plasma levels of glutamine decline, and this may affect the concentration of plasma IL-6 via a decrease in IL-6 synthesis and release from muscle. We hypothesized that glutamine supplementation would attenuate the exercise-induced decrease in plasma glutamine concentration and, thus, further enhance levels of plasma IL-6. Eight healthy men participated in a randomized, double-blind, crossover study in which they performed 2 h of cycle ergometry at 75% of peak O2 uptake. They received glutamine, glutamine-rich protein, or placebo supplementation at intervals during and 2 h after exercise. Exercise induced an 11-fold increase in plasma IL-6, which was further enhanced by glutamine (18-fold) and glutamine-rich protein (14-fold) supplementation, administered at doses that attenuated the exercise-induced decrease in plasma glutamine concentration.

Adult↗
PubMed2003

Searching for the exercise factor: is IL-6 a candidate?

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, one big challenge for muscle and exercise physiologists has been to determine how muscles signal to central and peripheral organs. Here we discuss the possibility that interleukin-6 (IL-6) could mediate some of the health beneficial effects of exercise. In resting muscle, the IL-6 gene is silent, but it is rapidly activated by contractions. The transcription rate is very fast and the fold changes of IL-6 mRNA is marked. IL-6 is released from working muscles into the circulation in high amounts. The IL-6 production is modulated by the glycogen content in muscles, and IL-6 thus works as an energy sensor. IL-6 exerts its effect on adipose tissue, inducing lipolysis and gene transcription in abdominal subcutaneous fat and increases whole body lipid oxidation. Furthermore, IL-6 inhibits low-grade TNF-alpha-production and may thereby inhibit TNF-alpha-induced insulin resistance and atherosclerosis development. We propose 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'.

Adipose Tissue↗
PubMed2003

Possible beneficial role of exercise in modulating low-grade inflammation in the elderly.

Aging is associated with increased levels of tumor necrosis factor-alpha (TNF) and interleukin (IL)-6. These two cytokines are tightly linked in that TNF induces production of IL-6, which again inhibits TNF gene expression. In epidemiological studies, both cytokines have been associated with obesity, insulin resistance and atherosclerosis. However, based on basal studies, we suggest that TNF (and not IL-6) is the driver behind insulin resistancy. Thus, it is possible that selective enhancement of the IL-6 level may inhibit TNF-induced insulin resistance. Muscle contractions induce production and release of IL-6, but not TNF, into the circulation, in both young and elderly humans. We suggest that muscle-derived IL-6 contributes to mediate the beneficial metabolic effects of exercise and may contribute to inhibit TNF-production and thereby insulin resistance.

Aged↗
PubMed2003

Association between fatigue and failure to preserve cerebral energy turnover during prolonged exercise.

AIM: This study evaluated if the fatigue and apathy arising during exercise with hypoglycaemia could relate to a lowering of the cerebral metabolic rates of glucose and oxygen. METHODS AND RESULTS: Six males completed 3 h of cycling with or without glucose supplementation in random order. Cerebral blood flow, metabolism and interleukin-6 (IL-6) release were evaluated with the Kety-Schmidt technique. Blood glucose was maintained during the glucose trial, while it decreased from 5.2 +/- 0.1 to 2.9 +/- 0.3 mmol L-1 (mean +/- SE) after 180 min of exercise in the placebo trial with a concomitant increase in perceived exertion (P < 0.05). During hypoglycaemia, the cerebral glucose uptake was reduced from 0.34 +/- 0.05 to 0.28 +/- 0.04 micromol g(-1) min(-1), while the cerebral uptake of beta-hydroxybutyrate increased to 5 +/- 1 pmol g(-1) min(-1) (P < 0.05). The reduced glucose uptake was accompanied by a lowering of the cerebral metabolic rate of oxygen from 1.84 +/- 0.19 mmol g(-1) min(-)1 during exercise with glucose supplementation to 1.60 +/- 0.16 mmol g(-1) min(-1) during hypoglycaemia (P < 0.05). In addition, the cerebral IL-6 release was reduced from 0.4 +/- 0.1 to 0.0 +/- 0.1 pg g(-1) min(-1) (P < 0.05). CONCLUSIONS: Exercise-induced hypoglycaemia limits the cerebral uptake of glucose, exacerbates exercise, reduces the cerebral metabolic rate of oxygen and attenuates the release of IL-6 from the brain.

3-Hydroxybutyric Acid↗
PubMed2003

Predicting death from tumour necrosis factor-alpha and interleukin-6 in 80-year-old people.

Ageing is associated with low-grade inflammation and markers such as IL-6 possess prognostic value. Tumour necrosis-alpha (TNF-alpha) initiates the inflammatory cascade and has been linked to several age-associated disorders. It remains, however, unknown if TNF-alpha is associated with mortality in old populations. The aim of the present study was to investigate if serum levels of TNF-alpha were associated with all-cause mortality independently of interleukin (IL)-6 in a prospective study of 333 relatively healthy 80-year-old people. A Cox regression model was used to explore effects of TNF-alpha and IL-6 on survival in the following 6 years. A total of 133 participants died during this follow-up period. TNF-alpha was associated with mortality in men, but not in women, whereas low-grade elevations in IL-6 were associated strongly with mortality in both sexes. TNF-alpha explained only 7% of the variability in IL-6 and effects of the two cytokines were independent of each other as well as of other traditional risk factors for death [smoking, blood pressure, physical exercise, total cholesterol, co-morbidity, body mass index (BMI) and intake of anti-inflammatory drugs]. These findings indicate that at least in old populations chronic elevated levels of TNF-alpha and IL-6 have different biological functions that trigger age-associated pathology and cause mortality.

Aged↗
PubMed2003

Circulating adiponectin levels during human endotoxaemia.

Adiponectin, an adipocytokine secreted by fat tissue, may prevent development of diabetes type II, as high adiponectin levels are linked with insulin sensitivity. In contrast, tumour necrosis factor (TNF)-alpha, which is also produced by fat tissue, leads to insulin resistance and furthermore inhibits adiponectin mRNA production and secretion of the protein. However, adiponectin also negatively regulates TNF-alpha levels. Therefore, we set out to test whether an infusion of endotoxin would influence circulating adiponectin levels in healthy human subjects. Twenty-three healthy human subjects were injected with endotoxin (2 ng/kg body weight); eight of these subjects were also injected with saline and served as controls. Plasma levels of adiponectin, TNF-alpha and interleukin-6 were measured at 0, 1.5, 2, 4, 8 and 24 h. TNF-alpha and interleukin-6 levels peaked at 1.5 h and 2 h, respectively. Control subjects injected with saline showed a decrease in adiponectin plasma levels with time (P < 0.05) presumably owing to the effect of fasting or physical inactivity. However, there was no change in adiponectin plasma levels in endotoxin injected subjects, thus the effect of fasting was opposed. In conclusion, circulating adiponectin levels are reduced during a resting and fasting state, an effect reversed by endotoxin injection.

Adiponectin↗
PubMed2003

T-cell receptor excisional circles, telomere length, proliferation and apoptosis in peripheral blood mononuclear cells of human immunodeficiency virus-infected individuals after 18 months of treatment induced viral suppression.

This study evaluated the effect of highly active antiretroviral therapy (HAART)-induced viral suppression on T-cell receptor excisional circles (TRECs), telomere length, proliferative responses and spontaneous as well as phytohaemagglutinin (PHA)-stimulated lymphocyte apoptosis in 27 human immunodeficiency virus (HIV)-infected individuals followed for 18 months during HAART. Our results show that HAART significantly increased the level of TRECs in CD4+ cells (P = 0.003) after 18 months of almost continuously suppressed HIV-RNA levels. Lymphocyte proliferative responses and apoptosis levels in patients were significantly lower and significantly higher, respectively, compared with healthy controls. The proliferative response and apoptosis levels did not change during follow up. Changes in telomere length were observed in CD4+ and in CD8+ T cells. The study demonstrated that HAART induces normal TREC levels in the CD4+ T-cell pool. However, the other perturbed functions in T cells indicate that immune reconstitution is incomplete and may need longer viral suppression.

Adult↗
PubMed2002

Is ageing associated with a shift in the balance between Type 1 and Type 2 cytokines in humans?

The balance between Type 1 and Type 2 cytokines is important for the outcome of several infectious diseases. As elderly humans show increased morbidity and mortality from infectious diseases, this study tests if ageing is associated with a change towards Type 2 dominance in T cells. Expression of IFN-gamma, and IL-4 was measured in CD4+ and CD8+ T cells by flow cytometry in three groups: young controls (n=28), 81-year-olds (n=22), and centenarians (n=25). The major findings were that the percentage of IFN-gamma+ as well as IL-4+ T cells was increased in aged subjects. Furthermore, after adjusting for decreased lymphocyte counts in the elderly, the concentration in the blood of IFN-gamma+ and IL-4+ CD8+ T cells was still increased in the 81-year-olds. In centenarians, a shift towards a relative dominance of Type 2 cytokine expression was found within CD8+ T cells. Furthermore, the percentage of T cells with cytokine expression was closely correlated to the in vivo expression of CD95 and CD45RO. In conclusion, we found some evidence for an age-related shift towards a Type 2 cytokine profile.

Adult↗
PubMed2002

Proliferation and telomere length in acutely mobilized blood mononuclear cells in HIV infected patients.

The aim of the study was to investigate the mobilization of T cells in response to a stressful challenge (adrenalin stimulation), and to access T cells resided in the peripheral lymphoid organs in HIV infected patients. Seventeen patients and eight HIV seronegative controls received an adrenalin infusion for 1 h. Blood was sampled before, during and 1 h after adrenalin infusion. Proliferation and mean telomere restriction fragment length (telomeres) of blood mononuclear cells (BMNC) and purified CD8+ and CD4+ cells were investigated at all time points. In patients, the proliferation to pokeweed mitogens (PWM) was lower and decreased more during adrenalin infusion. After adrenalin infusion the proliferation to PWM was restored only in the controls. In all subjects telomeres in CD4+ cells declined during adrenalin infusion. Additionally, the patients had shortened telomeres in their CD8+ cells, and particularly HAART treated patients had shortened telomeres in all cell-subtypes. The finding that patients mobilized cells with an impaired proliferation to PWM during and after adrenalin infusion has possible clinical relevance for HIV infected patients during pathological stressful conditions, such as sepsis, surgery and burns. However, this study did not find a correlation between impaired proliferation and telomeres. It is concluded that physiological stress further aggravates the HIV-induced immune deficiency.

Adult↗
PubMed2002

Activated T lymphocytes disappear from circulation during endotoxemia in humans.

Seventeen volunteers received an intravenous bolus of endotoxin (2 ng/kg of body weight). Endotoxin-induced lymphopenia was constituted mainly by cells with an immature phenotype (CD45RA(+) CD45RO(-)) that were less likely to undergo apoptosis (CD28(+)), whereas cells with the highest rates of disappearance were characterized by an activated phenotype (CD45RA(-) CD45RO(+)) as well as a phenotype linked to apoptosis (CD95(+) CD28(-)). In conclusion, endotoxin-induced lymphopenia reflects the disappearance from the circulation of activated lymphocytes prone to undergo apoptosis.

Adult↗
PubMed2001

Interleukin-6 production in contracting human skeletal muscle is influenced by pre-exercise muscle glycogen content.

1. Prolonged exercise results in a progressive decline in glycogen content and a concomitant increase in the release of the cytokine interleukin-6 (IL-6) from contracting muscle. This study tests the hypothesis that the exercise-induced IL-6 release from contracting muscle is linked to the intramuscular glycogen availability. 2. Seven men performed 5 h of a two-legged knee-extensor exercise, with one leg with normal, and one leg with reduced, muscle glycogen content. Muscle biopsies were obtained before (pre-ex), immediately after (end-ex) and 3 h into recovery (3 h rec) from exercise in both legs. In addition, catheters were placed in one femoral artery and both femoral veins and blood was sampled from these catheters prior to exercise and at 1 h intervals during exercise and into recovery. 3. Pre-exercise glycogen content was lower in the glycogen-depleted leg compared with the control leg. Intramuscular IL-6 mRNA levels increased with exercise in both legs, but this increase was augmented in the leg having the lowest glycogen content at end-ex. The arterial plasma concentration of IL-6 increased from 0.6 +/- 0.1 ng x l(-1) pre-ex to 21.7 +/- 5.6 ng x l(-1) end-ex. The depleted leg had already released IL-6 after 1 h (4.38 +/- 2.80 ng x min(-1) (P < 0.05)), whereas no significant release was observed in the control leg (0.36 +/- 0.14 ng x min(-1)). A significant net IL-6 release was not observed until 2 h in the control leg. 4. This study demonstrates that glycogen availability is associated with alterations in the rate of IL-6 production and release in contracting skeletal muscle.

Adult↗
PubMed2001

Transcriptional activation of the IL-6 gene in human contracting skeletal muscle: influence of muscle glycogen content.

In humans, the plasma interleukin 6 (IL-6) concentration increases dramatically during low-intensity exercise. Measurements across the working limb indicate that skeletal muscle is the source of IL-6 production. To determine whether energy availability influences the regulation of IL-6 expression during prolonged exercise, six male subjects completed two trials consisting of 180 min of two-legged dynamic knee extensor with either normal or low (~60% of control) pre-exercise muscle glycogen levels. Increases in plasma IL-6 during exercise were significantly higher (P<0.05) in the low-glycogen (16-fold) trial verses the control (10-fold) trial. Transcriptional activation of the IL-6 gene in skeletal muscle was also higher in the low-glycogen trial; it increased by about 40-fold after 90 min of exercise and about 60-fold after 180 min of exercise. Muscle IL-6 mRNA followed a similar but delayed pattern, increasing by more than 100-fold in the low-glycogen trial and by about 30-fold in the control trial. These data demonstrate that exercise activates transcription of the IL-6 gene in working skeletal muscle, a response that is dramatically enhanced when glycogen levels are low. These findings also support the hypothesis that IL-6 may be produced by contracting myofibers when glycogen levels become critically low as a means of signaling the liver to increase glucose production.

Exercise↗
PubMed2001

Muscle-derived interleukin-6: possible biological effects.

Interleukin-6 (IL-6) is produced locally in working skeletal muscle and can account for the increase in plasma IL-6 during exercise. The production of IL-6 during exercise is related to the intensity and duration of the exercise, and low muscle glycogen content stimulates the production. Muscle-derived IL-6 is released into the circulation during exercise in high amounts and is likely to work in a hormone-like fashion, exerting an effect on the liver and adipose tissue, thereby contributing to the maintenance of glucose homeostasis during exercise and mediating exercise-induced lipolysis. Muscle-derived IL-6 may also work to inhibit the effects of pro-inflammatory cytokines such as tumour necrosis factor alpha. The latter cytokine is produced by adipose tissue and inflammatory cells and appears to play a pathogenetic role in insulin resistance and atherogenesis.

Humans↗
PubMed2001

High levels of CD8-positive lymphocytes expressing CD45R0, granzyme B, and Ki-67 in lymph nodes of HIV-infected individuals are not associated with increased mortality.

Lymph nodes constitute the major site of HIV replication and of immunological response to HIV. To study the role of cytotoxic and mitotic active CD8(+) lymphocytes in lymph nodes during HIV infection we examined 28 formalin-fixed, paraffin-embedded lymph nodes sampled from 1984 to 1986 from 21 HIV-seropositive patients and seven HIV-negative patients. Eleven of the HIV-positive patients died within 78 months of biopsy time and 10 patients were alive on July 1, 1998. Double immunohistochemical staining procedures were developed to identify CD8(+) cells expressing CD45R0, granzyme B, and Ki-67. A stereological method was used to count the different cell types in the lymph nodes. There were no significant differences in the total cell (nucleated) and CD3(+) cell concentrations between the three groups. However, there were significantly higher concentrations of CD3(+)CD8(+), CD8(+)CD45R0(+), and CD8(+)Ki-67(+) lymphocytes in the HIV patients compared with the control group. Furthermore, there was a tendency for the HIV-deceased group to have lower levels of CD8(+)granzyme B(+) and CD8(+)Ki-67(+) lymphocyte concentrations compared with the HIV-alive group. Three HIV patients, who progressed to death within 49 months of biopsy time, were among the patients with the lowest concentrations of CD8(+)granzyme B(+) and CD8(+)Ki-67(+) lymphocytes. This finding allowed us to conclude that CD8(+) lymphocytes expressing high levels of CD45R0, granzyme B, and Ki-67 in lymph nodes of HIV patients are not related to increased mortality, whereas low concentrations of CD8(+) granzyme B(+) and CD8(+)Ki-67(+) lymphocytes may be associated with poor prognosis.

Adult↗