Increase In Plasma Interleukin-6 Research Articles

Oral post-treatment supplementation with a combination of glutamine, citrulline, and antioxidant vitamins additively mitigates jejunal damage, oxidative stress, and inflammation in rats with intestinal ischemia and reperfusion.

Intestinal ischemia and reperfusion (IIR) injury is closely associated with oxidative stress. Evidence shows that oral supplementation with glutamine and citrulline alleviates IIR-induced jejunal damage. We investigated the effects of a combination of glutamine, citrulline, and antioxidant vitamins on IIR-induced jejunal damage, oxidative stress, and inflammation. Male Wistar rats that underwent 60 min of superior mesenteric artery occlusion were orally administered glutamine plus citrulline (GC), vitamin C plus E (CE), or a combination of GC and CE 15 min before and 3, 9, and 21 h after reperfusion. Healthy rats without IIR were used as controls. After reperfusion for 24 h, rats with IIR showed lower levels of red blood cells, hemoglobin, serum glucose, and jejunal DNA and increased white blood cell counts compared to controls (1-way ANOVA with the least significant difference, P < 0.05). The IIR-induced decrease in serum albumin and increase in plasma interleukin-6 and jejunal thiobarbituric acid-reactive substances (TBARS) were significantly reversed by GC and/or CE. The results of the 2-way ANOVA indicated that GC was the main factor that increased jejunal villus height and muscularis DNA, and CE was the main factor that increased jejunal muscularis protein and decreased jejunal proinflammatory cytokine levels and myeloperoxidase activity. In addition, GC and CE are the main factors that decrease plasma proinflammatory cytokine levels and the jejunal apoptotic index. Oral post-treatment supplementation with glutamine and citrulline, combined with vitamins C and E, may alleviate IIR-induced oxidative stress, inflammation, and jejunal damage.

ANGPTL4, IL-6 and TNF-α as regulators of lipid metabolism during a marathon run

The aim of the study was to reveal whether marathon running influences regulators of lipid metabolism i.e. angiopoietin-like protein 4 (ANGPTL4), interleukin 6 (IL-6) and tumor necrosis factor-α (TNF-α). Plasma concentration of ANGPTL4, IL-6, TNF-α and lipids were determined in samples collected from 11 male runners before the marathon, immediately after the run and at 90 min of recovery. Plasma ANGPTL4 increased during exercise from 55.5 ± 13.4 to 78.1 ± 15.0 ng/ml (P < 0.001). This was accompanied by a significant increase in IL-6, TNF-α, free fatty acids (FFA) and glycerol (Gly) and a decrease in triacylglycerols (TG). After 90 min of recovery ANGPTL4 and TG did not differ from the exercise values, while plasma IL-6, TNF-α, FFA and Gly concentration were significantly lower. The exercise-induced increase in plasma concentration of ANGPTL4 correlated positively with the rise in plasma IL-6, TNF-α, FFA and Gly and negatively with the duration of the run. The increase in plasma IL-6 and TNF-α correlated positively with the rise in Gly. Summarizing, marathon running induced an increase in plasma ANGPTL4 and the value was higher in faster runners. The increase in plasma FFA, IL-6 and TNF-α concentration during a marathon run may be involved in plasma ANGPTL4 release, which could be a compensatory mechanism against FFA-induced lipotoxicity and oxidative stress. All of the analyzed cytokines may stimulate lipolysis during exercise.

Voluntary Exercise Eliminates Maternal Gestational Hypertension-Induced Hypertensive Response Sensitization to Postweaning High-Fat Diet in Male Adult Offspring.

Exercise has profound effects on cardiovascular function and metabolism in both physiological and pathophysiological states. The present study tested whether voluntary exercise would protect male offspring against maternal gestational hypertension-induced hypertensive response sensitization elicited by post-weaning high-fat diet (HFD). On low-lard-fat diet, offspring of both normotensive and hypertensive dams had comparable resting blood pressure, but HFD feeding elicited an enhanced increase in blood pressure (ie, hypertensive response sensitization) in sedentary offspring of hypertensive dams when compared with sedentary offspring of normotensive dams. The HFD fed sedentary offspring of hypertensive dams displayed greater sympathetic activity, enhanced pressor responses to centrally administered ANG II (angiotensin II) or leptin, and greater mRNA expression of proinflammatory cytokines, leptin, and a marker of blood-brain barrier leakage in the hypothalamic paraventricular nucleus. The enhanced blood pressure and central sympathetic activity in HFD-fed sedentary offspring of hypertensive dams were significantly reduced by exercise but fell only to levels comparable to HFD-fed exercising offspring of normotensive dams. HFD-induced increases in plasma IL-6 (interleukin-6) and sympathetic activity and greater pressor responses to central TNF (tumor necrosis factor)-α in offspring from both normotensive and hypertensive dams were also maintained after exercise. Nevertheless, exercise had remarkably beneficial effects on metabolic and autonomic function, brain reactivity to ANG II and leptin and gene expression of brain prohypertensive factors in all offspring. Voluntary exercise plays a beneficial role in preventing maternal hypertension-induced hypertensive response sensitization, and that this is associated with attenuation of enhanced brain reactivity and centrally driven sympathetic activity.

Pre-exercise Carbohydrate Drink Adding Protein Improves Post-exercise Fatigue Recovery.

Purpose: This study aimed to assess the requirement of protein in pre-exercise carbohydrate drinks for optimal endurance performance at high intensity and post-exercise fatigue recovery.Methods: Endurance performance at 85% peak of young men (age 20 ± 0.9 years, 2peak 49.3 ± 0.3 L/min) was measured for two consecutive days using cycling time to exhaustion and total work exerted 2 h after three isocaloric supplementations: RICE (50 g, protein: 1.8 g), n = 7; SOY + RICE (50 g, protein: 4.8 g), n = 7; and WHEY + RICE (50 g, protein: 9.2 g), n = 7.Results: Endurance performance was similar for the three supplemented conditions. Nevertheless, maximal cycling time and total exerted work from Day 1 to Day 2 were improved in the WHEY + RICE (+21%, p = 0.05) and SOY-RICE (+16%, p = 0.10) supplemented conditions, not the RICE supplemented condition. Increases in plasma interleukin-6 (IL-6) were observed 1 h after exercise regardless of supplemented conditions. Plasma creatine kinase remained unchanged after exercise for all three supplemented conditions. Increases in ferric reducing antioxidant power (FRAP) after exercise were small and similar for the three supplemented conditions.Conclusion: Adding protein into carbohydrate drinks provides no immediate benefit in endurance performance and antioxidant capacity yet enhances fatigue recovery for the next day. Soy-containing carbohydrate drink, despite 50% less protein content, shows similar fatigue recovery efficacy to the whey protein-containing carbohydrate drink. These results suggest the importance of dietary nitrogen sources in fatigue recovery after exercise.

Inhibition of early plasmin activation following thermal injury attenuates systemic inflammatory markers and inflammation within injured muscle

Introduction Burn injuries drive systemic inflammation, increasing the risk of organ dysfunction, and impeding the repair of injured tissues. Traumatic injuries provoke excess activation of plasmin, the protease responsible for degrading fibrin clots, causing bleeding complications. Although burn injuries rarely carry bleeding risks, excess plasmin activity can drive inflammatory signaling and vascular permeability, suggesting plasmin contributes to burn-induced inflammation. Therefore, we hypothesized that excess plasmin activation provoked by burn injury exacerbates inflammation at the site of tissue injury and systemically. Methods A validated, murine burn model in combination with muscle injury was employed to assess the study hypothesis. Sham animals received only calf muscle injuries. Mice expressing an NF-κB-inducible luciferase reporter were used to quantify inflammatory signaling by bioluminescence in tissues. To inhibit plasmin activity, mice received plasminogen antisense oligonucleotide (Plg ASO, IONIS Pharmaceuticals) before injury, or antifibrinolytic drug tranexamic acid (TXA) administered for 12 hours post-burn. Controls received control (Ctl) ASO or saline. Plasmin activation was measured by circulating complexes of plasmin and its inhibitor α2-antiplasmin (PAP). Inflammation was measured serially by plasma interleukin-6 (IL-6), neutrophil to lymphocyte ratio (NLR), and NF-κB activity in the injured muscle. Results Burn injury resulted in a 3-5 fold increase in plasmin activity measured by PAP(P<0.05) compared with sham animals and provoked a significant increase in plasma IL-6(P<0.005) and NLR(P<0.05) within 6-12 hours post-injury, at levels consistent with transient systemic inflammation. In mice without burns, muscle injury alone provoked NF-κB activity from 1-3 days post-injury with resolution by 5 days. With the addition of the burn injury, NF-κB activity within the injured calf muscle was significantly elevated between 1-3 days post-injury (P<0.01) and prolonged in the injured muscle (Figure 1). When plasmin was reduced with Plg ASO and TXA treatments, plasma IL-6 and NLR levels were reduced within 24 hours post-burn (P<0.05), and NF-κB activity within muscle was significantly reduced between 1-3 days post-burn (P<0.05)(Figure 1). Conclusion Burns provoke systemic and augment local inflammation in a muscle injury remote to the burn site. Inhibition of early plasmin activation after burn reduces systemic inflammatory markers and local inflammation within injured tissues. Significance Burn injuries incite significant global inflammation, increasing the risk of life-threatening complications, and chronic comorbidities. Because plasma drives inflammation after acute injury, it may be a therapeutic target to reduce tissue inflammation. However, plasmin is essential for fibrinolysis and tissue repair, and the beneficial effects of inhibiting plasmin following burn are likely time-dependent.

A non-linear mixed effect model for innate immune response: In vivo kinetics of endotoxin and its induction of the cytokines tumor necrosis factor alpha and interleukin-6.

Endotoxin, a component of the outer membrane of Gram-negative bacteria, has been extensively studied as a stimulator of the innate immune response. However, the temporal aspects and exposure-response relationship of endotoxin and resulting cytokine induction and tolerance development is less well defined. The aim of this work was to establish an in silico model that simultaneously captures and connects the in vivo time-courses of endotoxin, tumor necrosis factor alpha (TNF-α), interleukin-6 (IL-6), and associated tolerance development. Data from six studies of porcine endotoxemia in anesthetized piglets (n = 116) were combined and used in the analysis, with purified endotoxin (Escherichia coli O111:B4) being infused intravenously for 1–30 h in rates of 0.063–16.0 μg/kg/h across studies. All data were modelled simultaneously by means of importance sampling in the non-linear mixed effects modelling software NONMEM. The infused endotoxin followed one-compartment disposition and non-linear elimination, and stimulated the production of TNF-α to describe the rapid increase in plasma concentration. Tolerance development, observed as declining TNF-α concentration with continued infusion of endotoxin, was also driven by endotoxin as a concentration-dependent increase in the potency parameter related to TNF-α production (EC50). Production of IL-6 was stimulated by both endotoxin and TNF-α, and four consecutive transit compartments described delayed increase in plasma IL-6. A model which simultaneously account for the time-courses of endotoxin and two immune response markers, the cytokines TNF-α and IL-6, as well as the development of endotoxin tolerance, was successfully established. This model-based approach is unique in its description of the time-courses and their interrelation and may be applied within research on immune response to bacterial endotoxin, or in pre-clinical pharmaceutical research when dealing with study design or translational aspects.

Postexercise serum hepcidin response to repeated sprint exercise under normoxic and hypoxic conditions.

We determined the effects of repeated sprint exercise under normoxic and hypoxic conditions on serum hepcidin levels. Ten male athletes (age: 20.9 ± 0.3 years; height: 175.7 ± 6.0 cm; weight: 67.3 ± 6.3 kg) performed 2 exercise trials under normoxic (NOR; fraction of inspiratory oxygen (FiO2): 20.9%) or hypoxic conditions (HYPO; FiO2: 14.5%). The exercise consisted of 3 sets of 5 × 6 s of maximal pedaling (30-s rest periods between sprints, 10-min rest periods between sets). Blood samples were collected before exercise, immediately after exercise, and 1 and 3 h after exercise. Serum hepcidin levels were significantly elevated after exercise in both trials (both P < 0.01), with no significant difference between the trials. The postexercise blood lactate levels were significantly higher in the HYPO than the NOR (P < 0.05). Both trials caused similar increases in plasma interleukin-6 and serum iron levels (P < 0.001), with no significant difference between the trials. A significant interaction (trial × time) was apparent in terms of serum erythropoietin (EPO) levels (P = 0.003). The EPO level was significantly higher in the HYPO than the NOR at 3 h after exercise (P < 0.05). In conclusion, repeated sprint exercise significantly increased serum hepcidin levels to similar extent in 2 trials, despite differences in the inspired oxygen concentrations during both the exercise and the 3-h postexercise period.

Post-exercise serum hepcidin levels were unaffected by hypoxic exposure during prolonged exercise sessions.

The purpose of the present study was to determine the influence of hypoxic exposure during prolonged endurance exercise sessions (79 min in total) on post-exercise hepcidin levels in trained male endurance athletes. Ten endurance athletes (mean ± standard deviation; height: 169.8 ± 7.1 cm, weight: 57.1 ± 5.0 kg) conducted two endurance exercise sessions under either a normobaric hypoxic condition [inspired O2 fraction (FiO2) = 14.5%] or a normoxic condition (FiO2 = 20.9%). Exercise consisted of 10 × 3 min running on a treadmill at 95% of maximal oxygen uptake () with 60s of active rest at 60% of . After 10 min of rest, they subsequently performed 30 min of continuous running at 85% of . Running velocities were significantly lower in the HYPO than in the NOR (P < 0.0001). Exercise-induced blood lactate elevation was significantly greater in the HYPO (P < 0.01). There were significant increases in plasma interleukin-6, serum iron, and blood glucose levels after exercise, with no significant difference between the trials [interaction (trial × time) or main effect for trial, P > 0.05]. Serum hepcidin levels increased significantly 120 min after exercise (HYPO: from 10.7 ± 9.4 ng/mL to 15.8 ± 11.2 ng/mL; NOR: from 7.9 ± 4.7 ng/mL to 13.2 ± 7.9 ng/mL, P < 0.05), and no difference was observed between the trials. In conclusion, endurance exercise at lower running velocity in hypoxic conditions resulted in similar post-exercise hepcidin elevations as higher running velocity in normoxic conditions.

Acute Resistance Training Induced Increases in Plasma Interleukin-6 are Volume-dependent

Acute Resistance Training Induced Increases in Plasma Interleukin-6 are Volume-dependent

Exercise-mediated IL-6 signaling occurs independent of inflammation and is amplified by training in mouse adipose tissue.

The purpose of this investigation was to determine whether exercise-induced increases in adipose tissue interleukin 6 (IL-6) signaling occurred as part of a larger proinflammatory response to exercise and whether the induction of IL-6 signaling with acute exercise was altered in trained mice in parallel with changes in the IL-6 receptor complex. Sedentary and trained C57BL/6J mice were challenged with an acute bout of exercise. Adipose tissue and plasma were collected immediately and 4 h afterward and analyzed for changes in indices of IL-6 signaling, circulating IL-6, markers of adipose tissue inflammation, and expression/content of IL-6 receptor and glycoprotein 130 (gp130). In untrained mice, IL-6 mRNA increased immediately after exercise, and increases in indices of IL-6 signaling were increased 4 h after exercise in epididymal, but not inguinal adipose tissue. This occurred independent of increases in plasma IL-6 and alterations in markers of inflammation. When compared with untrained mice, in trained mice, acute exercise induced the expression of gp130 and IL-6 receptor alpha (IL-6Rα), and training increased the protein content of these. Acute exercise induced the expression, and training increased the protein content, of glycoprotein 130 and IL-6Rα and was associated with a more rapid increase in markers of IL-6 signaling in epididymal adipose tissue from trained compared with untrained mice. The ability of exogenous IL-6 to increase phosphorylation of STAT3 was similar between groups. Our findings demonstrate that acute exercise increases IL-6 signaling in a depot-dependent manner, likely through an autocrine/paracrine mechanism. This response is initiated more rapidly after exercise in trained mice, potentially as a result of increases in IL-6Rα and gp130.

Inhibition of HMGCoA reductase by simvastatin protects mice from injurious mechanical ventilation.

BackgroundMortality from severe acute respiratory distress syndrome exceeds 40% and there is no available pharmacologic treatment. Mechanical ventilation contributes to lung dysfunction and mortality by causing ventilator-induced lung injury. We explored the utility of simvastatin in a mouse model of severe ventilator-induced lung injury.MethodsMale C57BL6 mice (n = 7/group) were pretreated with simvastatin or saline and received protective (8 mL/kg) or injurious (25 mL/kg) ventilation for four hours. Three doses of simvastatin (20 mg/kg) or saline were injected intraperitoneally on days −2, −1 and 0 of the experiment. Lung mechanics, (respiratory system elastance, tissue damping and airway resistance), were evaluated by forced oscillation technique, while respiratory system compliance was measured with quasi-static pressure-volume curves. A pathologist blinded to treatment allocation scored hematoxylin-eosin-stained lung sections for the presence of lung injury. Pulmonary endothelial dysfunction was ascertained by bronchoalveolar lavage protein content and lung tissue expression of endothelial junctional protein Vascular Endothelial cadherin by immunoblotting. To assess the inflammatory response in the lung, we determined bronchoalveolar lavage fluid total cell content and neutrophil fraction by microscopy and staining in addition to Matrix-Metalloprotease-9 by ELISA. For the systemic response, we obtained plasma levels of Tumor Necrosis Factor-α, Interleukin-6 and Matrix-Metalloprotease-9 by ELISA. Statistical hypothesis testing was undertaken using one-way analysis of variance and Tukey’s post hoc tests.ResultsVentilation with high tidal volume (HVt) resulted in significantly increased lung elastance by 3-fold and decreased lung compliance by 45% compared to low tidal volume (LVt) but simvastatin abrogated lung mechanical alterations of HVt. Histologic lung injury score increased four-fold by HVt but not in simvastatin-pretreated mice. Lavage pleocytosis and neutrophilia were induced by HVt but were significantly attenuated by simvastatin. Microvascular protein permeability increase 20-fold by injurious ventilation but only 4-fold with simvastatin. There was a 3-fold increase in plasma Tumor Necrosis Factor-α, a 7-fold increase in plasma Interleukin-6 and a 20-fold increase in lavage fluid Matrix-Metalloprotease-9 by HVt but simvastatin reduced these levels to control. Lung tissue vascular endothelial cadherin expression was significantly reduced by injurious ventilation but remained preserved by simvastatin.ConclusionHigh-dose simvastatin prevents experimental hyperinflation lung injury by angioprotective and anti-inflammatory effects.

Heme oxygenase-1 induction by cobalt protoporphyrin enhances fever and inhibits pyrogenic tolerance to lipopolysaccharide

Heme oxygenase-1 (HO-1) is an enzyme that catalyzes degradation of the heme and regulates its availability for newly synthetized hemeproteins such as cyclooxygenases, NO synthases and cytochrome P450. Moreover, HO-1 activity modulates synthesis of cytokines and prostaglandins. All of these factors are well-defined components of fever and pyrogenic tolerance mechanisms. We examine the effect of HO-1 induction and activation using cobalt protoporphyrin (CoPP) on changes in body temperature (Tb), plasma levels of interleukin-6 (IL-6), prostaglandin E2 (PGE2) and HO-1 protein in the course of these processes. Intraperitoneally (i.p.) pre-treatment of rats with CoPP (5mgkg−1) significantly accelerated and enhanced the early stage of lipopolysaccharide (LPS)-induced fever and shortened a post-fever recovery to normal temperature. Pre-treatment with CoPP significantly potentiated the increase in plasma IL-6, PGE2 and HO-1 levels measured 4h after the LPS administration. Furthermore, induction of HO-1 attenuated the development of pyrogenic tolerance to repeated injections of LPS. Based on these data we conclude that heme oxygenase-1 may act as a physiological regulator of the febrile response intensity to bacterial infections.

Evidence for fatty acids mediating CL 316,243-induced reductions in blood glucose in mice.

CL 316,243, a β3-adrenergic agonist, was developed as an antiobesity and diabetes drug and causes rapid decreases in blood glucose levels in mice. The mechanisms mediating this effect have not been fully elucidated; thus, the purpose of the current study was to examine the role of fatty acids and interleukin-6, reputed mediators of insulin secretion, in this process. To address this question, we used physiological and pharmacological approaches in combination with knockout mouse models. CL 316,243 treatment in male C57BL6 mice increased plasma fatty acids, glycerol, interleukin-6, and insulin and reduced blood glucose concentrations 2 h following injections. The ability of CL 316,243 to increase insulin and fatty acids and reduce glucose was preserved in interleukin-6-deficient mice. CL 316,243-induced drops in blood glucose occurred in parallel with increases in circulating fatty acids but prior to increases in plasma interleukin-6. CL 316,243-mediated increases in plasma insulin levels and reductions in blood glucose were attenuated when mice were pretreated with the lipase inhibitor nicotinic acid or in whole body adipose tissue triglyceride lipase knockout mice. Collectively, our findings demonstrate an important role for fatty acids in mediating the effects of CL 316,243 in mice. Not only do our results provide new insight into the mechanisms of action of CL 316,243, but they also hint at an unappreciated aspect of adipose tissue -pancreas cross-talk.

Exercise training protects against an acute inflammatory insult in mouse epididymal adipose tissue

Exercise training reduces systemic and adipose tissue inflammation. However, these beneficial effects seem to be largely tied to reductions in adipose tissue mass. The purpose of the present study was to determine if exercise training confers a protective effect against an acute inflammatory challenge. We hypothesized that the induction of inflammatory markers, such as interleukin 6 (IL-6), suppressor of cytokine signaling 3 (SOCS3), and TNF-α by the beta-3 adrenergic agonist CL 316,243 would be reduced in adipose tissue from trained mice and this would be associated with reductions in transient receptor potential cation channel 4 (TRPV4), a protein recently shown to regulate the expression of proinflammatory cytokines. Exercise training (4 wk of treadmill running, 1 h/day, 5 days/wk) increased markers of skeletal muscle mitochondrial content and the induction of PPAR-gamma coactivator 1 alpha in epididymal adipose tissue. The mRNA expression of IL-6, SOCS3, and TNFα were not different in subcutaneous and epididymal adipose tissue from sedentary and trained mice; however, the CL 316,243-mediated induction of these genes was attenuated ∼50% in epididymal adipose tissue from trained mice as were increases in plasma IL-6. The effects of training were not explained by reductions in lipolytic responsiveness, but were associated with decreases in TRPV4 protein content. These results highlight a previously unappreciated anti-inflammatory effect of exercise training on adipose tissue immunometabolism and underscores the value of assessing adipose tissue inflammation in the presence of an inflammatory insult.

The effects of inspiratory muscle training on plasma interleukin-6 concentration during cycling exercise and a volitional mimic of the exercise hyperpnea

It is unknown whether the respiratory muscles contribute to exercise-induced increases in plasma interleukin-6 (IL-6) concentration, if this is related to diaphragm fatigue, and whether inspiratory muscle training (IMT) attenuates the plasma IL-6 response to whole body exercise and/or a volitional mimic of the exercise hyperpnea. Twelve healthy males were divided equally into an IMT or placebo (PLA) group, and before and after a 6-wk intervention they undertook, on separate days, 1 h of 1) passive rest, 2) cycling exercise at estimated maximal lactate steady state power (EX), and 3) volitional hyperpnea at rest, which mimicked the breathing and respiratory muscle recruitment patterns achieved during EX (HYPEX). Plasma IL-6 concentration remained unchanged during passive rest. The plasma IL-6 response to EX was reduced following IMT (main effect of intervention, P = 0.039) but not PLA (P = 0.272). Plasma IL-6 concentration increased during HYPEX (main effect of time, P < 0.01) and was unchanged postintervention. There was no evidence of diaphragm fatigue (measured by phrenic nerve stimulation) following each trial. In conclusion, plasma IL-6 concentration is increased during EX and HYPEX and this occurred in the absence of diaphragm fatigue. Furthermore, IMT reduced the plasma IL-6 response to EX but not HYPEX. These findings suggest that the respiratory muscles contribute to exercise-induced increases in plasma IL-6 concentration in the absence of diaphragm fatigue and that IMT can reduce the magnitude of the response to exercise but not a volitional mimic of the exercise hyperpnea.

Cardiotrophin-1 Is a Key Regulator of Glucose and Lipid Metabolism

Cardiotrophin-1 (CT-1) is a member of the gp130 family of cytokines. We observed that ct-1(-/-) mice develop mature-onset obesity, insulin resistance, and hypercholesterolemia despite reduced calorie intake. Decreased energy expenditure preceded and accompanied the development of obesity. Acute treatment with rCT-1 decreased blood glucose in an insulin-independent manner and increased insulin-stimulated AKT phosphorylation in muscle. These changes were associated with stimulation of fatty acid oxidation, an effect that was absent in AMPKα2(-/-) mice. Chronic rCT-1 treatment reduced food intake, enhanced energy expenditure, and induced white adipose tissue remodeling characterized by upregulation of genes implicated in the control of lipolysis, fatty acid oxidation, and mitochondrial biogenesis and genes typifying brown fat phenotype. Moreover, rCT-1 reduced body weight and corrected insulin resistance in ob/ob and in high-fat-fed obese mice. We conclude that CT-1 is a master regulator of fat and glucose metabolism with potential applications for treatment of obesity and insulin resistance.

Systemic Effects of White Adipose Tissue Dysregulation and Obesity‐Related Inflammation

Systemic Effects of White Adipose Tissue Dysregulation and Obesity‐Related Inflammation

Role of Antioxidant Supplementation on Training-induced IL-6

Antioxidant supplementation has been shown to attenuate the acute exercise-induced increase in plasma interleukin-6 (IL-6). PURPOSE: To investigate the effect of antioxidants on the regulation of IL-6 expression in muscle and circulation in response to acute exercise before and after high-intensity endurance exercise training. METHODS: Twenty-one young healthy men were allocated into either an antioxidant (AO; vitamin C and E) or a placebo (PL) group. A 1h-acute bicycling exercise trial at 65% of maximal power output was performed before and after 12 weeks of progressive endurance exercise training. Blood samples and muscle biopsies were taken pre and immediately after cessation of exercise, and at 3h of recovery period. RESULTS: The acute exercise-induced plasma IL-6 increase was blunted after the training period in the PL group (P<0.05) but not in the AO group. Endurance exercise training lowered resting levels and attenuated the acute exercise-induced increase in muscle-IL-6 mRNA in both groups. There was an overall increase in skeletal muscle oxidative stress as evaluated by malondialdehyde (MDA) with training in the AO group compared with PL (P<0.05). This was accompanied by a general increase in skeletal muscle mRNA expression of antioxidative enzymes, including catalase (CAT), copper-zinc superoxide dismutase (CuZnSOD) and glutathione peroxidase 1 (GPX1) mRNA expression in the AO group. However, skeletal muscle protein content of catalase, CuZnSOD, or GPX1 was not affected by training or supplementation. CONCLUSIONS: Vitamin C and E supplementation blunts the training-induced lowering of exercise-induced increase in plasma IL-6, possibly through increased oxidative stress in the trained state.

Resistance Training at Eight-Repetition Maximum Reduces the Inflammatory Milieu in Elderly Women

Inflammatory cytokines are associated with age- and inactivity-related diseases. We examined the influence of moderate- to high-intensity resistance trainings (RT) on inflammatory cytokines (interleukin 6 (IL-6) and 1beta (IL-1beta) and tumor necrosis factor alpha (TNF-alpha)) in circulation and lipopolysaccharide (LPS)-stimulated whole blood in elderly women. Previously sedentary women (72 +/- 6.1 yr) were grouped according to their hormone replacement regimen: traditional estrogen/progesterone (HRT, n = 12), selective estrogen receptor modulator (SER, n = 7), no hormone replacement (NHR, n = 9), or nonexercise control group taking no hormone replacement (CON, n = 7). Participants in the HRT, SER, and NHR groups trained (three sets, 10 exercises at eight-repetition maximum (8RM)) 3 d x wk(-1), whereas participants in the CON group maintained their "normal" activity for 10 wk. Participants performed a bout of resistance exercise (RE at 8RM; HRT, SER, and NHR groups) or sat quietly (CON) before (BT) and after (AT) RT to assess the influence of training on the acute responses to RE. Blood samples were obtained preexercise (PR), postexercise (PO), and 2 h postexercise (2H; same time points for resting CON). Hormone status had no influence on dependent variables, so HRT, SER, and NHR groups were collapsed into one exercise group (EX, n = 28) and compared with CON. RT significantly reduced resting serum TNF-alpha level by 37%. RT also reduced LPS-stimulated production of IL-6, IL-1beta, and TNF-alpha at all time points (PR, PO, and 2H; per monocyte). Acute RE transiently increased plasma TNF-alpha, but blunted the circadian increase in LPS-stimulated inflammatory cytokines observed in CON. The blunting effect in EX was significantly greater AT compared with BT. RE also resulted in an increase in plasma IL-6, which was significantly reduced AT (BT: PR = 1.6 +/- 0.5, PO = 2.8 +/- 0.5; AT: PR = 1.8 +/- 0.3, PO = 2.4 +/- 0.3). We found that 10 wk of moderate- to high-intensity RT 1) reduced the systemic inflammatory milieu and 2) abrogated exercise-induced circulating IL-6 in previously sedentary elderly women.

Hypothermia increases interleukin-6 and interleukin-10 in juvenile endotoxemic mice*

To develop a juvenile mouse model to establish effects of in vivo hypothermia on expression of the inflammation-modulating cytokines tumor necrosis factor-alpha, interleukin-1beta, interleukin-6, and interleukin-10. Although induced hypothermia is neuroprotective in some patients, the mechanisms of protection are not well understood and concerns remain over potential detrimental effects, particularly in the setting of infection. We previously showed that in vitro hypothermia increases production of tumor necrosis factor-alpha and interleukin-1beta in lipopolysaccharide-treated monocytes. : Laboratory investigation. Research laboratory. Juvenile (4-wk) male C57BL/6 mice. : Mice were given chlorpromazine to suspend thermoregulation and lipopolysaccharide to stimulate cytokine production. Core temperature was maintained at 32 degrees C or 37 degrees C for 6 hrs by adjusting environmental temperature. In separate experiments, lipopolysaccharide-treated mice were kept in a cooling chamber without chlorpromazine treatment. Plasma and organs were collected for cytokine quantitation. Chlorpromazine-treated hypothermic mice had 2.3-fold and 1.8-fold higher plasma interleukin-6 and interleukin-10 levels at 6 hrs compared with identically treated normothermic mice (p < .05), whereas plasma tumor necrosis factor-alpha and interleukin-1beta were not significantly different at 2 hrs or 6 hrs. Liver tumor necrosis factor-alpha and interleukin-6 were significantly higher in hypothermic vs. normothermic mice, but lung and brain cytokines were not different. Lipopolysaccharide-treated mice kept in a cooling chamber without chlorpromazine treatment developed varying degrees of hypothermia with associated increases in plasma interleukin-6 and interleukin-10. A nonspecific marker of stress (plasma corticosterone) was not affected by hypothermia in lipopolysaccharide-treated mice. Further studies are necessary to determine the mechanism and physiologic consequences of augmented systemic interleukin-6 and interleukin-10 expression during induced hypothermia.