Response of plasma IL-6 and its soluble receptors during submaximal exercise to fatigue in sedentary middle-aged men

The pleiotropic cytokine interleukin-6 (IL-6) has been demonstrated to increase during exercise. Little is known regarding the response of the soluble IL-6 receptors (sIL-6R and sgp130) during such exercise. The aim of the current study was to investigate the response of plasma IL-6, sIL-6R and sgp130 during fatiguing submaximal exercise in humans. Twelve participants underwent an incremental exercise test to exhaustion and one week later performed a submaximal exercise bout (96 ± 6% lactate threshold) to volitional exhaustion. Blood samples taken at rest and immediately post exercise were analyzed for IL-6, sIL-6R and sgp130. IL-6 increased (P < 0.01) by 8.4 ± 8.9 pg ml⁻¹ (75.7%) during the exercise period. sIL-6R and sgp130 also increased (P < 0.05) by 2.7 ± 3.9 ng ml⁻¹ (9.6%) and 37.7 ± 55.6 ng ml⁻¹ (9.6%), respectively. The current study is the first investigation to demonstrate that alongside IL-6, acute exercise stress results in an increase in both sIL-6R and sgp130.     

Substrate use during and following moderate- and low-intensity exercise: Implications for weight control

Substrate utilization during and after low- and moderate-intensity exercise of similar caloric expenditure was compared. Ten active males [age: 26.9 (4.8) years; height: 181.1 (4.8) cm; Mass: 75.7 (8.8) kg; maximum O₂ consumption (V˙O_{2 max} ): 51.2 (4.8) ml · kg⁻¹ · min⁻¹] cycled at 33% and 66% V˙O_{2 max} on separate days for 90 and 45 min, respectively. After exercise, subjects rested in a recumbent position for 6 h. Two h post-exercise, subjects ate a standard meal of 66% carbohydrate (CHO), 11% protein, and 23% fat. Near-continuous indirect calorimetry and measurement of urinary nitrogen excretion were used to determine substrate utilization. Total caloric expenditure was similar for the two trials; however, significantly (P<0.05) more fat [42.4 (3.6) g versus 24.0 (12.2) g] and less CHO [142.5 (28.5) g versus 188.8 (45.2) g] was utilized as a substrate during the low-intensity compared to the moderate-intensity trial. Protein utilization was similar for the two trials. The difference in substrate use can be attributed to the exercise period because over twice as much fat was utilized during low-intensity [30.0 (11.0) g] compared to moderate-intensity exercise [13.6 (6.6) g]. Significantly more (P<0.05) CHO was utilized during the moderate-intensity [106.0 (27.8) g] compared to the low-intensity exercise [68.7 (20.0) g]. Substrate use during the recovery period was not significantly different. We conclude that low-intensity, long-duration exercise results in a greater total fat oxidation than does moderate intensity exercise of similar caloric expenditure. Dietary-induced thermogenesis was not different for the two trials. Accepted: 3 November 1997     

The effect of repeated endurance exercise on IL-6 and sIL-6R and their relationship with sensations of fatigue at rest

Strenuous, prolonged exercise increases interleukin-6 (IL-6) release. The effect of IL-6 is dependent on the availability of IL-6 receptors. Few studies have addressed the impact of exercise on IL-6 receptor levels or procalcitonin (PCT), an indicator of systemic inflammation. Changes in these molecules may give insight into cytokine-related mechanisms underlying exercise-related fatigue. Thirteen trained male subjects partook in the study. They cycled a total distance of 468 km over 6 days. Blood samples were obtained prior to and immediately following Day 1 of the study and then each morning prior to exercise. Blood samples were analysed for plasma IL-6, soluble IL-6 receptor (sIL-6R), C-reactive protein (CRP), PCT, creatine kinase (CK) and cortisol concentrations. Subjects also completed mood state questionnaires each day prior to exercise. IL-6 was elevated immediately post-exercise on Day 1 but was unchanged at rest for the duration of the event. In contrast, sIL-6R, CRP, PCT and CK concentrations were unchanged immediately post-exercise on Day 1 but were significantly elevated at rest over the duration of the event compared with pre-event baseline. sIL-6R was highly correlated to CRP. Cortisol concentrations remained unchanged at all time points. In conclusion, strenuous, prolonged exercise stimulated an acute phase response which was maintained throughout the 6-day event. sIL-6R increase is associated with CRP and may affect subjective sensations of post-exercise fatigue at rest.     

The effect of a thiamin derivative on exercise performance

The purpose of this study was to investigate the effect of a thiamin derivative, thiamin tetrahydrofurfuryl disulfide (TTFD), on oxygen uptake (˙VO₂), lactate accumulation and cycling performance during exercise to exhaustion. Using a randomized, double-blind, cross-over design with a 10-day washout between trials, 14 subjects ingested either 1 g · day⁻¹ of TTFD or a placebo (PL) for 4 days. On day 3, subjects performed a progressive exercise test to exhaustion on a cycle ergometer for the determination of ˙VO_2submax, ˙VO_2peak, lactate concentration ([La⁻ ]), lactate threshold (Th_La) and heart rate ( f _c). On day 4, subjects performed a maximal 2000-m time trial on a cycle ergometer. A one-way analysis of variance (ANOVA) with repeated measures was used to determine significant differences between trials. There were no significant differences detected between trials for serial measures of ˙VO_2submax, [La⁻] or f _c. Likewise, ˙VO_2peak [PL 4.06 (0.19) TTFD 4.12 (0.19) l · min⁻¹, P = 0.83], Th_La [PL 2.47 (0.17), TTFD 2.43 (0.16) l · min⁻¹, P = 0.86] and 2000-m performance time [PL 204.5 (5.5), TTFD 200.9 (4.3) s, P = 0.61] were not significantly different between trials. The results of this study suggest that thiamin derivative supplementation does not influence high-intensity exercise performance. Accepted: 19 December 1996     

The effects of high-intensity intermittent exercise on the plasma concentrations of glutamine and organic acids

Glutamine is an essential substrate for the proper functioning of cells of the immune system. Falls in plasma glutamine concentration after exercise may have deleterious consequences for immune cell function and render the individual more susceptible to infection. The purpose of the present study was to examine changes in plasma glutamine concentration (measured using a validated enzymatic spectrophotometric method) following an acute bout of intermittent high-intensity exercise. Eight well-trained male games players took part in the study. Subjects reported to the laboratory following an overnight fast and performed a 1-h cycle exercise task consisting of 20 1-min periods at 100% maximal O₂ consumption (V˙O_2max) each separated by 2 min of recovery at 30% V˙O_2max. Venous blood samples were taken before exercise and at 5 min, 1 h, 2.5 h, 5 h and 24 h post-exercise. Glutamine was measured by enzymatic spectrophotometric determination of the ammonia concentration before and after treatment of the plasma with glutaminase (EC 3.5.1.2). Plasma glutamine concentration did not fall in the immediate post-exercise period [pre-exercise 681 (23) μM compared with 663 (46) μM at 5 min post-exercise, mean (SEM)], but fell to 572 (35) μM at 5 h post-exercise (P < 0.05 compared with pre-exercise). Plasma lactate concentration rose to 8.8 (1.0) mM at the end of exercise and fell to 1.8 (0.4) mM at 1 h post-exercise, but plasma concentrations of free fatty acids and β-hydroxybutyrate both rose substantially in the post-exercise period (to 240% and 400% of pre-exercise levels, respectively). The circulating leucocyte count increased significantly during exercise (P < 0.01), continued to increase in the hours following exercise and peaked at 2.5 h post-exercise (mainly due to a neutrophilia). The fall in the plasma glutamine concentration at 5 h post-exercise could be due to increased renal uptake of glutamine, which generally occurs in conditions of metabolic acidosis or due to a greater removal of glutamine from the plasma resulting from the elevated circulating leucocyte count. Accepted: 22 October 1997     

Effects of artificially-induced anaemia on sudomotor and cutaneous blood flow responses to heat stress

The influence of artificially induced anaemia on thermal strain was evaluated in trained males. Heat stress trials (38.6°C, water vapour pressure 2.74 kPa) performed at the same absolute work rates [20 min of seated rest, 20 min of cycling at 30% peak aerobic power (V˙O_2peak), and 20 min cycling at 45% V˙O_2peak] were completed before (HST1) and 3–5 days after 3 units of whole blood were withdrawn (HST2). Mild anaemia did not elevate thermal strain between trials, with auditory canal temperatures terminating at 38.5°C [(0.16), HST1] and 38.6°C [(0.13), HST2; P > 0.05]. Given that blood withdrawal reduced aerobic power by 16%, this observation deviates from the close association often observed between core temperature and relative exercise intensity. During HST2, the absolute and integrated forearm sweat rate (m˙ _sw) exceeded control levels during exercise (P < 0.05), while a suppression of forehead m˙ _sw occurred (P < 0.05). These observations are consistent with a possible peripheral redistribution of sweat secretion. It was concluded that this level of artificially induced anaemia did not impact upon heat strain during a 60-min heat stress test. Accepted: 17 April 1997     

The development of an isokinetic squat device: reliability and relationship to functional performance

The aims of the present study were: (1) to assess aerobic metabolism in paraplegic (P) athletes (spinal lesion level, T4–L3) by means of peak oxygen uptake (V˙O_2peak) and ventilatory threshold (VT), and (2) to determine the nature of exercise limitation in these athletes by means of cardioventilatory responses at peak exercise. Eight P athletes underwent conventional spirographic measurements and then performed an incremental wheelchair exercise on an adapted treadmill. Ventilatory data were collected every minute using an automated metabolic system: ventilation (l · min⁻¹), oxygen uptake (V˙O₂, l · min⁻¹, ml · min⁻¹ · kg⁻¹), carbon dioxide production (V˙CO₂, ml · min⁻¹), respiratory exchange ratio, breathing frequency and tidal volume. Heart rate (HR, beats · min⁻¹) was collected with the aid of a standard electrocardiogram. V˙O_2peak was determined using conventional criteria. VT was determined by the breakpoint in the V˙CO₂−V˙O₂ relationship, and is expressed as the absolute VT (V˙O₂, ml · min⁻¹ · kg⁻¹) and relative VT (percentage of V˙O_2peak). Spirometric values and cardioventilatory responses at rest and at peak exercise allowed the measurement of ventilatory reserve (VR), heart rate reserve (HRr), heart rate response (HRR), and O₂ pulse (O₂ P). Results showed a V˙O_2peak value of 40.6 (2.5) ml · min⁻¹ · kg⁻¹, an absolute VT detected at 23.1 (1.5) ml · min⁻¹ · kg⁻¹ V˙O₂ and a relative VT at 56.4 (2.2)% V˙O_2peak. HRr [15.8 (3.2) beats · min⁻¹], HRR [48.6 (4.3) beat · l⁻¹], and O₂ P [0.23 (0.02) ml · kg⁻¹ · beat⁻¹] were normal, whereas VR at peak exercise [42.7 (2.4)%] was increased. As wheelchair exercise excluded the use of an able-bodied (AB) control group, we compared our V˙O_2peak and VT results with those for other P subjects and AB controls reported in the literature, and we compared our cardioventilatory responses with those for respiratory and cardiac patients. The low V˙O_2peak values obtained compared with subject values obtained during an arm-crank exercise may be due to a reduced active muscle mass. Absolute VT was somewhat comparable to that of AB subjects, mainly due to the similar muscle mass involved in wheelchair and arm-crank exercise by P and AB subjects, respectively. The increased VR, as reported in patients with chronic heart failure, suggested that P athletes exhibited cardiac limitation at peak exercise, and this contributed to the lower V˙O_2peak measured in these subjects. Accepted: 22 April 1997     

Recombinant human interleukin-6 infusion during low-intensity exercise does not enhance whole body lipolysis or fat oxidation in humans

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 ergometry at 70% peak O(2) consumption (Vo(2 peak); MOD) and 40% Vo(2 peak) with (LOW + IL-6) and without (LOW) infusion of recombinant human (rh)IL-6. The dose of rhIL-6 during LOW + IL-6 elicited IL-6 concentration similar to those during MOD but without altering the circulating hormonal milieu seen in MOD. Palmitate rate of appearance (R(a)), rate of disappearance (R(d)), and oxidation were measured by means of a constant infusion of [U-(13)C]palmitate (0.015 micromol.kg(-1).min(-1), prime NaHCO(3), 1 micromol/kg). Palmitate R(a), R(d), and oxidation were not affected by rhIL-6 infusion, remaining similar to LOW at all times. Palmitate R(a) and oxidation were significantly greater in the MOD trial (P < 0.05) compared with the LOW + IL-6 and LOW trials. Our 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. These data 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.     

Prolonged intermittent high intensity exercise impairs neuromuscular performance of the knee flexors

This study investigated the effect of prolonged intermittent high intensity exercise upon the isokinetic leg strength and electromechanical delay of the knee flexors. Seven male collegiate soccer players were exposed to: (i) a prolonged intermittent high intensity exercise task (PIHIET) which required subjects to complete a single-leg pedalling task, with the preferred limb, (75 rpm for all constant-load portions of the task) consisting of 48 × 1.8 minute cycles of exercise, and (ii) a control task consisting of no exercise. Pre-, mid- and post-PIHIET gravity corrected indices of knee flexion angle-specific torque (0.44 rad knee flexion (AST); 0 rad = full knee extension; [1.05 rad · s⁻¹]) were made for both intervention and control limbs. Electromechanical delay (EMD) of the m. biceps femoris during supine knee flexion movements was evaluated in the preferred leg on both intervention and control days. Repeated measures ANOVAs revealed significant condition (intervention; control) by time (pre; mid; post) interactions for both knee flexor AST (F_[2,12] = 4.8; p<0.03) and EMD (F_[2,12] = 4.1; p<0.05). AST was observed to decrease by 16% and EMD increase by 30% pre to post intervention. These observations suggest an impairment of neuromuscular control and the ability to maintain force generation in the knee flexors, near the extremes of the range of motion during prolonged intermittent high-intensity exercise activities. Changes of this magnitude may pose a threat to the integrity of the knee joint. Accepted: 6 January 1998     

Interleukin-6 receptor signaling. II. Bio-availability of interleukin-6 in serum.

Interleukin-6 (IL-6) is used as a growth factor by various tumor cells. It binds to a gp80 specific receptor (IL-6R) and then to a gp130 transducing chain. Both receptor chains are released as soluble functional proteins which circulate in biological fluids. With a view to studying the physiological role of these soluble receptors, both proteins were purified from human plasma. Surface plasmon resonance was used to measure the kinetic constants of equilibria between IL-6 and natural sIL-6R, and between the IL-6/sIL-6R complex and soluble gp130. Kd values were found to be 0. 9 and 2.3 nM respectively. Soluble natural IL-6R and gp130 were also found to interact with a Kd of 2.8 nM in the absence of IL-6. By using these Kd values, a mathematical simulation predicted that 1) within a large range of IL-6, sIL-6R and sgp130 concentrations, free IL-6 represents 30% of the total circulating cytokine, 2) sIL-6R overconcentrations lead to dramatic changes of the concentration of free IL-6, 3) increased concentrations of sgp130 should produce an efficient buffering effect on the IL-6/sIL-6R complex without incidence on the level of free IL-6. According to this model, the IL-6/sIL-6R complex appears to be an important support of IL-6 signaling in the most commonly encountered in vivo situations. The concentration of this complex is directly under the control of the concentration of sIL-6R; its bio-availability should be efficiently buffered by increased sgp130 concentrations.     

Gp130 activation by soluble interleukin-6 receptor/interleukin-6 enhances osteoblastic differentiation of human bone marrow-derived mesenchymal stem cells

Interleukin-6 (IL-6) promotes osteodifferentiation in bone-located progenitors; however, it is not known whether this cytokine affects the differentiation of bone marrow-located osteoprogenitors. To address this issue, we prepared human bone marrow-derived mesenchymal stem cells (MSCs), which were characterized by a cell surface phenotype and multipotential nature. It was observed that in the presence of IL-6, MSCs were not differentiated into the osteogenic lineage, as evidenced by a failure to induce alkaline phosphatase activity, an earlier marker of osteodifferentiation. The lack of effect of IL-6 correlates with the observation that MSCs do not express a membrane-bound or soluble IL-6 receptor (sIL-6R). The incompetence of IL-6 was not reversed by the addition of sIL-6R alone or the sIL-6R/IL-6 complex, as it occurs in other IL-6R-negative cells. However, after MSC osteocommittment by dexamethasone, sIL-6R or the sIL-6R/IL-6 complex enhanced alkaline phosphatase activity. The effect of sIL-6R or sIL-6R/IL-6 proved to be dependent on gp130 availability, which is expressed by MSCs, and involves stat-3 phosphorylation. These data suggest that IL-6R deficiency may represent for bone marrow-located mesenchymal progenitors a sort of protective mechanism to escape the osteogenic effect of IL-6, which is produced by the MSC itself as well as by other marrow stromal cells.     

Inflammatory cytokines and metabolic responses to high-intensity intermittent training: effect of the exercise intensity

To examine the effects of two high-intensity intermittent training (HIIT) programs of varying intensities (100% vs. 110% of maximal aerobic velocity [MAV]) on metabolic, hormonal and inflammatory markers in young men. Thirty-seven active male volunteers were randomly assigned into: HIIT experimental groups (100% MAV [EG₁₀₀, n = 9] and 110% MAV [EG₁₁₀, n = 9]) and a control groups (CG₁₀₀, n = 9 and CG₁₁₀, n = 9). Particpants performed high intesity intermittent exercise test (HIIE) at 100% or 110% MAV. Venous blood samples were obtained before, at the end of HIIE and at 15 min of recovery, and before and after 8 weeks of HIIT programs. After training, Glucose was lower (p < 0.01) in EG₁₀₀ (d = 0.72) and EG₁₁₀ (d = 1.20) at the end of HIIE, and at 15 min recovery only in EG₁₁₀ (d = 0.95). After training, Insulin and Cortisol were lower than before training in EG₁₀₀ and EG₁₁₀ at the end of HIIE (p < 0.001). After HIIT, IL-6 deceased (p < 0.001) in EG₁₀₀ (d = 1.43) and EG₁₁₀ (d = 1.56) at rest, at the end of HIIE (d = 1.03; d = 1.75, respectively) and at 15 min of recovery (d = 0.88;d = 1.7, respectively). This decrease was more robust (p < 0.05) in EG₁₁₀ compared to EG₁₀₀. After HIIT, TNF-α deceased (p < 0.001) in EG₁₀₀ (d = 1.43) and EG₁₁₀ (d = 0.60) at rest, at the end of HIIE (0.71 < d < 0.98) and at 15 min of recovery (0.70 < d < 2.78). HIIT with 110% MAV is more effective in young males on the improvements of some metabolic (Glucose), hormonal (Cortisol) and inflammatory (IL-6) markers at rest, at the end of HIIE and 15 min of recovery than training at 100 % MAV.     

Reduced performance of male and female athletes at 580 m altitude

This study examined the effect of mild hypobaria (MH) on the peak oxygen consumption (O_2peak) and performance of ten trained male athletes [ (SEM); O_2peak = 72.4 (2.2) ml · kg⁻¹ · min⁻¹] and ten trained female athletes [O_2peak = 60.8 (2.1) ml · kg⁻¹ · min⁻¹]. Subjects performed 5-min maximal work tests on a cycle ergometer within a hypobaric chamber at both normobaria (N, 99.33 kPa) and at MH (92.66 kPa), using a counter-balanced design. MH was equivalent to 580 m altitude. O_2peak at MH decreased significantly compared with N in both men [− 5.9 (0.9)%] and women [− 3.7 (1.0)%]. Performance (total kJ) at MH was also reduced significantly in men [− 3.6 (0.8)%] and women [− 3.8 (1.2)%]. Arterial oxyhaemoglobin saturation (S_aO₂) at O_2peak was significantly lower at MH compared with N in both men [90.1 (0.6)% versus 92.0 (0.6)%] and women [89.7 (3.1)% versus 92.1 (3.0)%]. While S_aO₂ at O_2peak was not different between men and women, it was concluded that relative, rather than absolute, O_2peak may be a more appropriate predictor of exercise-induced hypoxaemia. For men and women, it was calculated that 67–76% of the decrease in O_2peak could be accounted for by a decrease in O₂ delivery, which indicates that reduced O₂ tension at mild altitude (580 m) leads to impairment of exercise performance in a maximal work bout lasting ≈ 5 min. Accepted: 30 July 1996     

Association between heart rate variability and training response in sedentary middle-aged men

The effect of exercise training on heart rate variability (HRV) and improvements in peak oxygen consumption ( _peak) was examined in sedentary middle-aged men. The HRV and absolute and relative _peak of training (n = 19) and control (n = 15) subjects were assessed before and after a 24-session moderate intensity exercise training programme. Results indicated that with exercise training there was a significantly increased absolute and relative _peak (P < 0.005) for the training group (12% and 11% respectively) with no increase for the control group. The training group also displayed a significant reduction in resting heart rate; however, HRV remained unchanged. The trained subjects were further categorized into high (n = 5) and low (n = 5) HRV groups and changes in _peak were compared. Improvements in both absolute and relative _peak were significantly greater (P > 0.005) in the high HRV group (17% and 20% respectively) compared to the low HRV group (6% and 1% respectively). The groups did not differ in mean age, pretraining oxygen consumption, or resting heart rate. These results would seem to suggest that a short aerobic training programme does not alter HRV in middle-aged men. Individual differences in HRV, however, may be associated with _peak response to aerobic training.     

Effect of the melanocortin-3 receptor Thr6Lys and Val81Ile genetic variants on body composition and substrate oxidation in Chilean obese children

Mice genetically deficient in the melanocortin-3 receptor gene are characterized by normal body weight, increased body fat, mild hypophagia, reduced locomotor activity, and increased respiratory quotient compared with wild-type mice. In humans, the 6Lys–81Ile haplotype of melanocortin-3 receptor (MC3R) gene has been associated with childhood obesity, higher body fat percentage, and reduced fat oxidation compared to non-carriers. The aim of this study was to evaluate the association between MC3R 6Lys–81Ile haplotype with body composition and substrate oxidation in response to moderate exercise in obese children. Eight Chilean obese children (aged 8–12) carriers of MC3R 6Lys–81Ile haplotype were compared with eight age–gender-matched obese non-carriers. Children were identified through a previous cross-sectional study on genetic determinants of childhood obesity (n = 229). Genotypes for MC3R Thr6Lys and Val81Ile were determined by polymerase chain reaction–restriction fragment length polymorphism. Body composition was assessed by the four-compartment model (dual-energy X-ray absorptiometry, total body water by the deuterium dilution technique, and total fat mass by air-displacement plethysmography). Substrate oxidation was assessed by indirect calorimetry in response to moderate exercise (60% VO_{2 max}). Wilcoxon matched-pairs test was used to compare quantitative variables. No significant differences among carriers and non-carriers were found in anthropometrical and body composition measurements. The Carriers of the 6Lys–81Ile haplotype showed higher respiratory quotient (p = 0.06) and a significantly higher glucose oxidation (p = 0.01) compared with non-carriers after standardization for fat-free mass. Our results are consistent with a possible participation of MC3R 6Lys–81Ile variants in glucose oxidation in response to moderate exercise.     

Serum levels of interleukin-6 type cytokines and soluble interleukin-6 receptor in patients with rheumatoid arthritis.

We investigated the serum concentrations of interleukin-6 (IL-6) and two IL-6 family of cytokines (leukaemia inhibitory factor (LIF) and ciliary neurotrophic factor (CNTF) as well as IL-6 soluble receptor (sIL-6R) using an enzyme-linked immunosorbent assay (ELISA) in 66 patients with rheumatoid arthritis (RA) and 24 healthy controls. We examined a possible association between the serum levels of these peptides and RA activity according to the Mallya and Mace scoring system and Ritchie''s index. We also evaluated the correlation between the serum levels of IL-6, LIF, CNTF and sIL-6R and duration of the disease and calculated sIL-6R/IL-6 ratio in RA patients and in the control group. IL-6 and sIL-6R were detectable in all 66 patients with RA and 24 normal individuals. LIF was also found in the serum of all patients with RA and in 16 (66.7%) normal individuals. In contrast CNTF was measurable only in 15 (22.7%) patients with RA and 24 (33.3%) normal individuals. The highest IL-6 and sIL-6R levels were found in the patients with Stages 3 and 4 of RA activity and the lowest in the control group. In contrast there were no statistically significant differences between the LIF and CNTF levels in RA patients and normal individuals. We found positive correlation between IL-6 and sIL-6R concentrations and Ritchie''s index and a lack of such correlation with LIF and CNTF. IL-6 serum level correlated positively with the disease duration, but sIL-6R, LIF and CNTF did not. Serum sIL-6R/IL-6 ratio was significantly lower in RA patients than in healthy controls. In conclusion, an increase in the serum levels of IL-6 and sIL-6R, but not LIF and CNTF concentrations, may be useful markers for RA activity.     

Structure-guided optimization of the interleukin-6 trans-signaling antagonist sgp130

Binding of interleukin-6 (IL-6) to its specific receptor IL-6R is a prerequisite for the activation of the signal-transducing receptor glycoprotein 130 (gp130). A soluble form of the IL-6R (sIL-6R) in complex with IL-6 can activate cells lacking membrane-bound IL-6R (trans-signaling). IL-6-trans-signaling is counterbalanced by a naturally occurring, soluble form of gp130 (sgp130), whereby signaling via the membrane-bound IL-6R is not affected. Many inflammatory and neoplastic disorders are driven by IL-6 trans-signaling. By analysis of the three-dimensional structure of gp130 in complex with IL-6 and sIL-6R, we identified amino acid side chains in gp130 as candidates for the generation of sgp130 muteins with increased binding affinity to IL-6/sIL-6R. In addition, with information from modeling and NMR analysis of the membrane proximal domain of gp130, we generated a more stable variant of sgp130Fc. Proteins were tested for binding to the IL-6/sIL-6R-complex, for inhibition of IL-6/sIL-6R-induced cell proliferation and of acute phase gene expression. Several mutations showed an additive effect in improving the binding affinity of human sgp130 toward human IL-6/sIL-6R. Finally, we demonstrate the species specificity of these mutations in the optimal triple mutein (T102Y/Q113F/N114L) both in vitro and in a mouse model of acute inflammation.     

The effect of severe eccentric exercise-induced muscle damage on plasma elastase, glutamine and zinc concentrations

The aim of this study was to determine if severe exercise-induced muscle damage alters the plasma concentrations of glutamine and zinc. Changes in plasma concentrations of glutamine, zinc and polymorphonuclear elastase (an index of phagocytic cell activation) were examined for up to 10 days following eccentric exercise of the knee extensors of one leg in eight untrained subjects. The exercise bout consisted of 20 repetitions of electrically stimulated eccentric muscle actions on an isokinetic dynamometer. Subjects experienced severe muscle soreness and large increases in plasma creatine kinase activity indicative of muscle fibre damage. Peak soreness occurred at 2 days post-exercise and peak creatine kinase activity [21714 (6416) U · l⁻¹, mean (SEM)] occurred at 3 days post-exercise (P < 0.01 compared with pre-exercise). Plasma elastase concentration was increased at 3 days post-exercise compared with pre-exercise (P < 0.05), and is presumably indicative of ongoing phagocytic leucocyte infiltration and activation in the damaged muscles. There were no significant changes in plasma zinc and glutamine concentrations in the days following eccentric exercise. We conclude that exercise-induced muscle damage does not produce changes in plasma glutamine or zinc concentrations despite evidence of phagocytic neutrophil activation. Accepted: 3 November 1997