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Cytokine Responses to Treadmill Running in Healthy and Illness-Prone Athletes


Medicine & Science in Sports & Exercise: November 2007 - Volume 39 - Issue 11 - p 1918-1926
doi: 10.1249/mss.0b013e318149f2aa
CLINICAL SCIENCES: Clinically Relevant

Purpose: To characterize differences in cytokine responses to exercise of different intensities and durations between healthy and illness-prone runners.

Methods: Trained distance runners were classified as healthy (no more than two episodes of upper-respiratory symptoms per year; N = 10) or illness-prone (four or more episodes per year; N = 8) and completed three treadmill tests: SHORT (30 min, 65% V˙O2max), LONG (60 min, 65% V˙O2max), and INTENSE (6 × 3 min, 90% V˙O2max). Blood samples were collected pre-, post-, 1 h, 10 h, and 24 h after exercise, and interleukin (IL)-2, IL-4, IL-6, IL-8, IL-10, IL-12, and IL-1ra concentrations were determined. Repeated-measures ANOVA was used to assess changes in cytokine responses to exercise. Magnitudes of changes and differences between groups were characterized using Cohen's effect size (ES) criteria.

Results: Resting IL-8, IL-10, and IL-1ra concentrations were 19-38% lower (ES:0.38-0.96; small to moderate differences) in illness-prone runners. Similarly, postexercise IL-10 concentrations were 13-20% lower (ES: 0.20-0.37; small differences), and IL-1ra concentrations were 10-20% lower (ES: 0.22-0.38; small differences) in illness-prone subjects. In contrast, IL-6 elevations were 84-185% higher (ES: 0.29-0.59, small differences) in illness-prone subjects. Postexercise responses of IL-2, IL-4, and IL-12 were small and not substantially different between the groups.

Conclusions: Cytokine responses to controlled treadmill running differ between healthy and illness-prone athletes. Illness-prone distance runners showed evidence suggestive of impaired inflammatory regulation in the hours after exercise that may account for the greater frequency of upper-respiratory symptoms experienced.

1Department of Physiology, Australian Institute of Sport, Canberra, AUSTRALIA; 2School of Biomedical Sciences, Faculty of Health, University of Newcastle, Callaghan, AUSTRALIA; and 3Medical School, The Australian National University, Canberra, AUSTRALIA

Address for correspondence: Ms. Amanda Cox, Department of Physiology, Australian Institute of Sport, PO Box 176, Belconnen ACT 2616, Australia; E-mail:

Submitted for publication January 2007.

Accepted for publication June 2007.

Postexercise changes in cytokine kinetics are likely to play an important role in modulating some of the reported postexercise changes in immune function. Various events trigger cytokine responses to exercise, including microtrauma to muscle and connective tissue (2,12,23). However, cytokine responsiveness in the absence of muscle damage (9,25) indicates that other mechanisms are involved. Regardless of the initial trigger, acute and transient increases in plasma concentrations of IL-6 postexercise mediate changes in other pro- (27) and antiinflammatory (21,24) cytokines. Postexercise increases in IL-8 (11,13,29) are likely to influence neutrophil chemotactic properties and inflammation at sites of local production, while increases in antiinflammatory IL-10 and IL-1ra presumably elicit a counterregulatory, antiinflammatory response (11,15,29). The protracted nature of the antiinflammatory cytokine response (20) alludes to the importance of a counterregulatory antiinflammatory response in restoring homeostasis.

Although there have been a large number of investigations characterizing immune responses to exercise in healthy subjects, to date there have been no attempts to directly compare the magnitude and time course of immune responses to exercise between healthy and illness-prone athletes. Disruptions in immunoregulatory cytokines have been implicated as contributing to the postexercise period of increased illness susceptibility (18); however, it remains unclear whether illness-prone athletes experience greater disruptions in immune function after prolonged or intensive exercise.

Most studies of cytokine responses to exercise have focused on marathon and ultramarathon events (11,15). The extensive muscle damage incurred in these races is likely to amplify the magnitude of any postexercise changes in immune regulation (12,28). Although athletes may experience URS after such competitions, illness-prone athletes may also be susceptible to URS after regular training activities or increases in training load (5). Surprisingly, cytokine responses to more moderate exercise loads, representative of routine training activities, are not as well characterized, and there have been few attempts to directly compare the effects of varying exercise loads (16). Those studies that have examined cytokine responses to more moderate exercise loads, including a 60-min treadmill run (14) and water polo training (10), report changes of smaller magnitude in comparison with the long-distance events. Extended-duration exercise studies are difficult to replicate, and the results may not directly transfer to the majority of sporting and recreational settings. For this reason, further examination of cytokine responses to more moderate exercise is warranted.

Disruptions in the balance between pro- and antiinflammatory cytokines may lead to a loss of inflammatory control, with possible implications for overall immune system function. It remains unclear whether repeated, exercise-induced changes in cytokine and immune responsiveness, particularly in individuals undertaking multiple training sessions in a single day, contribute to a greater rate of illness susceptibility in some athletes. Investigation of differences in immune and inflammatory responses to exercise in athletes with or without recurrent URS is required to either support or refute this association. Examination of inflammatory control in athletes may contribute to a clearer understanding of the mechanism underlying susceptibility to URS, and other cytokine-mediated illnesses, in athletic populations, and assist sports physicians in better management of illness-prone athletes. The aim of this study was to determine whether cytokine responses differ between healthy and illness-prone runners after treadmill running representative of typical training loads. A secondary aim was to quantify, in a dose-dependant manner, the effects of moderate, intense, and longer-duration treadmill running exercise on cytokine responses.

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Eighteen well-trained, male, middle- or long-distance runners aged 31.2 ± 8.2 yr (mean ± SD) were recruited into the study. Subjects were assigned to either healthy or illness-prone groups according to the number of self-reported episodes of URS in the preceding 12 months. Athletes were categorized as healthy if they had two or fewer episodes of URS (N = 10) or as illness prone if they reported four or more episodes of URS in the preceding 12 months (N = 8). Physical, training, and maximal performance characteristics of the cohort are shown in Table 1. The study was undertaken with approval of the ethics committees of the University of Newcastle, Hunter Area Health Service, and Australian Institute of Sport. All subjects provided written informed consent before participation.



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Exercise testing.

The maximal aerobic capacity (V˙O2max) of each subject was assessed by an incremental treadmill test to volitional exhaustion, using methods similar to those described previously (3). The maximal component of the test involved subjects running at 14 km·h−1 (0% gradient), with increases in speed of 1 km·h−1 each minute until a speed of 18 km·h−1 was reached. Beyond this, the gradient was increased by 1% each minute until volitional exhaustion. The time taken (min) to reach volitional exhaustion was recorded as the maximal performance time. V˙O2max was determined as the highest 60-s oxygen consumption value recorded. Heart rate was measured using a Polar S810 heart rate monitor (Polar,Kempele, Finland), and capillary blood lactate concentration was determined on completion of the test using a handheld Lactate Pro analyzer (Arkray Inc, Kyoto, Japan). The oxygen-consumption values recorded during the submaximal component of the treadmill test were used to plot a linear regression of running speed versus oxygen consumption, from which running speeds corresponding to 65% and 90% of V˙O2max were calculated. These running speeds were rounded to the nearest 0.5 km·h−1 and were used for each individual's subsequent treadmill running protocols.

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Study design.

Athletes completed three treadmill running tests in a randomized and counterbalanced order, with each test separated by a minimum of 1 wk. The tests were: (i) 30 min running at 65% V˙O2max (SHORT), (ii) 60 min at 65% V˙O2max (LONG), and (iii) 6 × 3 min intervals at 90% V˙O2max, with 90 s of active recovery between each repetition (INTENSE). Subjects presented to the laboratory on the morning of their allocated testing day after a light breakfast and having refrained from exercise for the previous 12 h. A resting blood sample (PRE) was collected 10 min before commencement of the exercise protocol. Subjects were allowed a maximum of 5 min to warm up on the treadmill at a self-selected speed slower than that set for completion of the exercise protocol. Heart rate (HR) was monitored continuously during the exercise protocol, and, on completion, subjects assessed their effort using Borg's Rating of Perceived Exertion (RPE) scale of 6-20. Each exercise protocol was only undertaken if the individual athlete was free of illness symptoms on the scheduled testing day.

Immediately after completion of the exercise protocol, a second blood sample was collected (POST). Athletes were then required to sit quietly for 1 h, after which a third blood sample was collected (1 h). The consumption of water ad libitum was allowed for the first 50 min of this 1-h recovery period. Subjects returned to the lab at 10 and then 24 h after completion of the exercise test for collection of additional blood samples. Diet and fluid consumption were not monitored during this period of absence from the laboratory, but athletes were instructed to refrain from further exercise training until after the collection of the 24 h sample. All blood samples were collected from a superficial forearm vein, using standard venipuncture techniques, with subjects in a supine position.

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Determination of plasma cytokine concentrations.

Blood samples were collected directly into K3EDTA tubes (Greiner Bio-one; Frickenhausen, Germany). Plasma was separated by centrifugation at 4000 rpm for 5 min and was stored frozen at −80°C until analysis. Plasma concentrations of IL-6 and IL-8 (proinflammatory cytokines), IL-10 and IL-1ra (antiinflammatory cytokines), and IL-2, IL-4, and IL-12 (immunoregulatory cytokines) were determined simultaneously using a Bio-Plex Suspension Array System (Bio-Rad Laboratories Pty Ltd; Hercules, CA) and custom-manufactured Multiplex Cytokine Kits (Bio-Rad Laboratories Pty Ltd; Hercules, CA). Assays were completed according to the manufacturer's instructions, using a series of seven unique premixed and prelabeled bead sets. Samples were diluted 1:2 in the provided sample diluent and were assayed in duplicate along with a pair of quality controls. A series of eight standards of known cytokine concentrations were included in each assay for the following ranges: IL-2: 0.13-2050.0 pg·mL−1, IL-4: 0.03-552.4 pg·mL−1, IL-6: 0.26-4336.2 pg·mL−1, IL-8: 0.22-3626.5 pg·mL−1, IL-10: 0.28-4537.7 pg·mL−1, IL-12: 0.23-3752.3 pg·mL−1, IL-1ra: 0.23-3711.1 pg·mL−1. Assay plates were washed by vacuum filtration, using the provided wash buffer and a Multiscreen Resist Vacuum Manifold (Millipore; Billerica, MA), so that beads were retained within each well during the assay. All samples from individual subjects were analyzed in a single assay to avoid interassay variation.

The Bio-Plex Suspension Array reader (Bio-Rad Laboratories Pty Ltd; Hercules, CA) was calibrated each day before use. Identification of bead subsets and measurement of fluorescence intensity was determined for each well by the suspension array reader. A standard curve of cytokine concentration as a function of fluorescence units was constructed using Bio-Plex Manager Version 4.0 Software (Bio-Rad Laboratories Pty Ltd; Hercules, CA). Cytokine concentrations for each sample were then determined by extrapolation from the respective standard curve using recorded fluorescence values.

For each of the seven cytokines, results from each assay were accepted if the correlation coefficient for the standard curve was greater than 0.98 and if positive controls were within two standard deviations from their established mean concentration. The coefficients of variation (CV) for the low and high controls, respectively, were, for IL-2, 6.3 and 7.0%; IL-4, 9.8 and 11.3%; IL-6, 9.1 and 4.6%; IL-8, 10.8 and 3.2%; IL-10, 9.6 and 4.5%; IL-12, 8.1 and 5.8%; and IL-1ra, 5.9 and 5.7%.

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Statistical analysis.

Descriptive statistics (mean ± SD) were used to summarize the physical and performance characteristics of the cohort. Cytokine concentrations were nonnormally distributed and log-transformed before analysis. Differences in the performance measures between healthy and illness-prone groups were evaluated using an unpaired t-test, as were baseline cytokine concentrations. Cytokine responses to the three treadmill running protocols were assessed using a three-factor (TIME × GROUP × PROTOCOL) repeated-measures analysis of variance (ANOVA). Post hoc analysis (Tukey HSD) was undertaken to identify any specific differences. All analyses were undertaken using the statistical package STATISTICA 6.0 (StatSoft Inc; Tulsa, OK), with significance accepted at P < 0.05. Below P = 0.01, P values have been reported as P < 0.01.

Standardized mean changes (1) were used to characterize (i) the acute effects of exercise on cytokine responses, and (ii) differences in the cytokine responses between the groups for each of the protocols. A modification of Cohen's effect size classification system (trivial: 0.0-0.2; small: 0.2-0.6; moderate: 0.6-1.2; large: 1.2-2.0) was used to interpret the magnitude of observed changes. Ninety-percent confidence intervals (± 90% CI) were calculated to indicate the precision of the estimate of observed effects and to determine whether effects (both increases/decreases in response to exercise and differences between groups) were equivocal or unequivocal in nature. Qualitative descriptors were then applied to describe likely effects as either (i) trivial; (ii) small/moderate/large increases, decreases or differences where appropriate; or (iii) unclear (if confidence intervals spanned substantial positive and substantial negative values).

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Exercise Performance

There were no significant differences in physical attributes, training history, or performance ability between the healthy and illness-prone groups (Table 1). There were no significant differences between the groups in the performance (treadmill velocity and distance covered) or the physiological demands (HR and RPE) of any of the three tests (Table 2). On this basis, differences in workload were excluded as a potential confounding variable for any differences in cytokine measures between groups.



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Cytokine Responses to Short, Long, and Intense Treadmill Running Protocols

The acute effects of three different controlled doses of exercise on cytokine responses were assessed independently of the subject's illness history. Concentrations of IL-2 and IL-4 were not substantially affected by any of the treadmill running protocols. In contrast, changes in IL-12, IL-6 and IL-8, and IL-10 and IL-1ra concentrations were observed at POST and at 1 h for the three treadmill tests (Table 3). The postexercise increases in IL-6, IL-8, and IL-10 and the decreases in IL-12 were typically ameliorated at 10 and 24 h. For IL-6, IL-8, and IL-12, neither the patterns nor the magnitudes of responses were significantly different between the three protocols. In contrast, both the pattern and magnitudes of change in IL-10 concentrations varied significantly (P < 0.01) between protocols (Table 3).



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Preexercise Cytokine Concentrations for Healthy and Illness-Prone Runners

The PRE cytokine concentrations were compared for healthy and illness-prone groups (Table 4). There were no significant differences in baseline IL-2, IL-4, IL-6, or IL-12 cytokine concentrations between the groups. In contrast, the mean IL-8, IL-10, and IL-1ra concentrations were all substantially lower (~20-40%) at rest in the illness-prone compared with the healthy athletes.



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Cytokine Responses of Healthy and Illness-Prone Runners to 60 min of Treadmill Running

Immunoregulatory cytokines IL-2, IL-4, and IL-12.

The effect of illness history on cytokine responses to exercise was determined by identifying the presence or absence of divergent patterns between the healthy and illness-prone athletes. IL-2 and IL-4 concentrations did not vary significantly in response to 60-min treadmill running and were not significantly different between the groups at any time point. Unlike all other cytokines, the concentration of IL-12 was typically reduced in both healthy and illness-prone groups after 60 min of treadmill running, although the PRE to POST decrease in IL-12 concentrations was, on average, 20% greater (ES: 0.31 ± 0.54, unclear) among the healthy group. Mean effects suggested small differences between the groups, but associated imprecision in the estimate resulted in an "unclear" classification.

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Proinflammatory cytokines IL-6 and IL-8.

The IL-6 concentrations varied significantly in the 24 h after the completion of the LONG treadmill running protocol, with postexercise increases of approximately 10-fold (P < 0.01; ES: 1.14 ± 0.56, moderate to large increase) for the illness-prone group and approximately fivefold (P = 0.02; ES: 0.67 ± 0.43, small to moderate increase) for the healthy group. Magnitudes of increase in IL-6 concentrations were 2.2-fold greater immediately postexercise (ES: 0.38 ± 0.67, unclear) and 1.9-fold greater at 1 h postexercise (ES: 0.31 ± 0.67, unclear) in the illness-prone compared with the healthy group (Fig. 1A). Mean effects suggested small differences between the groups, but associated uncertainty resulted in "unclear' classifications. Greater magnitudes of increase in IL-6 concentrations were similarly observed in the illness-prone group in response to INTENSE, but not SHORT, treadmill running (data not shown).



IL-8 concentrations varied significantly during the 24-h period after the LONG treadmill protocol for both the healthy (P < 0.01) and illness-prone groups (P < 0.01) (Fig. 1B). Concentrations increased by up to 32% (ES: 0.92 ± 0.25, moderate increase) at 1 h after exercise before returning to or falling below preexercise levels at 24 h. There were no substantial differences in the magnitudes of the IL-8 response to exercise between the groups, and the approximately 20% higher concentration observed in healthy athletes before exercise was maintained at 24 h (ES: 0.86 ± 0.74, trivial to large difference). A similar trend for higher IL-8 concentrations in healthy athletes was observed after the INTENSE and the SHORT protocol.

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Antiinflammatory cytokines-IL-10 and IL-1ra.

In response to the LONG treadmill protocol, IL-10 concentrations increased by about 70% (range of ES: 0.75-1.30, moderate to large increases) in both the healthy and illness-prone groups at POST before returning to preexercise levels by 24 h (Fig. 2A). Although IL-10 responses were not substantially different between the groups, IL-10 concentrations remained, on average, up to 30% higher (ES: 0.62 ± 0.99, unclear) among the healthy athletes at 1 h, with mean effects suggesting a moderate difference between the groups, despite the unclear confidence interval. Higher IL-10 concentrations were also noted in healthy athletes in response to the INTENSE treadmill protocol, where the magnitudes of increase in IL-10 concentrations were higher for the healthy athletes, both immediately after exercise (ES: 0.22 ± 0.30, trivial to small increase) and after 1 h of recovery (ES: 0.41 ± 0.51, trivial to small increase).



IL-1ra concentrations varied significantly in response to the LONG treadmill protocol for both healthy (P < 0.01) and illness-prone groups (P < 0.01), increasing immediately after exercise, before declining to below preexercise concentrations at 24 h (Fig. 2B). Even at 24 h, IL-1ra concentrations remained, on average, 40% higher (P = 0.03)among healthy compared with illness-prone athletes (ES: 1.12 ± 0.82, small to large difference). Despite the differences in absolute concentrations, the magnitudes of change in IL-1ra concentrations in response to the LONG treadmill protocol were not substantially different between the groups. In contrast, after the INTENSE treadmill protocol, absolute IL-1ra concentrations were higher (range of ES: 0.87-1.29, moderate to large differences) and magnitudes of increase were greater (range of ES: 0.22-0.42, small differences) in the healthy compared with the illness-prone group.

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This study provides evidence of divergent cytokine profiles between healthy and illness-prone distance runners. Specifically, there was evidence of lower resting IL-8, IL-1ra, and IL-10 concentrations and the possibility of a more potent IL-6 response to 60-min treadmill running in illness-prone compared with healthy athletes. These differences may reflect an altered state of inflammatory control amongst the illness-prone group, possibly contributing to the increased rates of URS in these individuals. In addition, this study systematically characterized the cytokine responses triggered by exercise typical of the day-to-day training loads of distance runners as opposed to the completion of particularly strenuous long-distance races. Although there was some imprecision in these estimates of altered cytokine responsiveness, results from this study provide a framework for further investigations of the causes of recurrent or persistent URS in athletic populations.

The lower absolute concentrations of IL-10, IL-1ra, and IL-8, combined with the greater postexercise elevations in IL-6, highlight a potential for excessive inflammatory responses among illness-prone athletes. This potential seems to be the result of a seemingly inadequate antiinflammatory capacity, and it may elicit dysregulated inflammatory control. IL-6 has been previously recognized as a trigger for the production of antiinflammatory cytokines IL-4 (22), IL-10, and IL-1ra (21,24,27). Despite the more pronounced IL-6 response observed in the illness-prone group, we actually observed lower concentrations of antiinflammatory cytokines both before and after exercise in these athletes compared with the healthy controls. One possible explanation for this may be that the IL-6 stimulus was insufficient to induce marked perturbations in IL-10 and IL-1ra. However, given the observations from the healthy group, this contention does not seem to be the case. Instead, we speculate that a possible defect in antiinflammatory responsiveness is evident in this cohort of illness-prone distance runners. Further interpretation of these results is limited by the absence of clearly defined reference ranges for cytokine concentrations in healthy individuals atrest, in different clinical conditions, and in response to various forms of exercise.

The IL-6 response to exercise is the most well characterized of all the cytokines. In the current study, the baseline IL-6 concentrations were similar to other reports of being towards the lower limits of assay detection (29). Likewise, the postexercise increases (up to about 10-fold) are broadly in line with other studies reporting modest, approximately fivefold, increases immediately after a 60-min treadmill run at 75% V˙O2max (14) and approximately eightfold increases after 60 min of eccentric lower-limb exercise (30). The magnitude of the response to moderate-intensity treadmill running observed here was considerably lower than after marathon (13,15) and ultramarathon (11) events, where up to 125-fold elevations in IL-6 have been reported (12). In combination, these data support a dose-response relationship between postexercise cytokine responses and exercise load (duration and intensity). Muscle damage and tissue-repair processes are one likely explanation for the very large increases in cytokine concentrations after long-distance races. The design of the current study focused on activities representative of typical day-to-day training undertaken by distance runners, and it provides a more realistic picture of the immune perturbations that are likely to be experienced with regular training activities.

In the current study, the magnitude of the IL-6 response differed between healthy and illness-prone groups in response to 60 min of treadmill running. The higher IL-6 concentration observed in the illness-prone group suggests that this group should experience a more potent stimulus for release of the antiinflammatory cytokines IL-10 and IL-1ra. However, IL-10 and IL-1ra concentrations were actually lower in the illness-prone group. This raises the possibility of impaired antiinflammatory responses or poorly regulated cytokine balance in this group. In keeping with the literature (20), postexercise increases in IL-6 were typically ameliorated by 24 h after exercise among the healthy athletes. However, in the illness-prone group, IL-6 concentrations were still 130% above baseline after 24 h of recovery, providing further evidence of dysregulated inflammatory control among the illness-prone runners.

Despite attempts to control for the possible effects of diurnal variation and other pretest variables, there was large interindividual variation in the patterns and magnitudes of the IL-6 response, and considerable uncertainty was associated with the estimates of IL-6 responsiveness to LONG treadmill running described earlier. Whereas the mean response was a 2.2-fold greater postexercise elevation in IL-6 for the illness-prone group, responses ranged from small decreases to large increases. Considering the key role that has been ascribed to IL-6 in driving cytokine responses to exercise (21), further studies are required to more fully characterize the physiological relevance of potential differences between healthy and illness-prone groups.

Considering the differences in IL-6 responses between healthy and illness-prone groups, the IL-8 concentrations for the two groups were somewhat unexpected, particularly considering the well-recognized properties of IL-8 as a chemotactic factor for neutrophils (8) potentiating inflammation at sites of local production. The resting IL-8 concentrations in the current study were consistent with earlier reports in an athletic population (29). The influence of exercise load on the magnitude of cytokine response was evident in the modest changes observed in this study compared with those reported after extended-duration racing (12,26). Unexpectedly, IL-8 concentrations were up to 30% lower at baseline and after exercise for illness-prone subjects. Enhanced neutrophil recruitment in healthy subjects would be advantageous in instances of infection. In addition, with neutrophils recently being recognized as a source of soluble cytokine receptors (7) and antiinflammatory microvesicles (6), their enhanced recruitment potential under the influence of IL-8 may be important in the local regulation of impending inflammatory events. In the current study, where the lower IL-8 concentrations observed in the illness-prone group suggest a lesser propensity for neutrophil recruitment, subsequent regulation of inflammatory homeostasis may be similarly compromised.

Antiinflammatory cytokines are as important as proinflammatory cytokines in controlling inflammatory responses. In the current study, baseline IL-10 concentrations were comparable with those from existing studies (15,23), but they were about 35% higher in healthy compared with illness-prone athletes. The magnitudes of increase in IL-10 concentration of up to 70% were similar between the groups, but they were substantially lower than those reported after marathon (13,22,26) and ultramarathon events (11), where up to 27-fold elevations have been reported (15). In addition to higher baseline concentrations, postexercise IL-10 concentrations remained about 25% higher in the healthy group, despite the more pronounced IL-6 response of the illness-prone group. Considering the well-documented actions of IL-10 as a key antiinflammatory factor (19), a compromised IL-10 response in illness-prone subjects may be interpreted as an indicator of a dysregulated antiinflammatory response in these athletes.

There is a wide range of IL-1ra concentrations reported in the literature. The IL-1ra concentrations observed in the current study were similar to some reports (20,29) but were lower than others (12). The postexercise increases of about 40% in IL-1ra were markedly lower than other studies involving more moderate-type exercise (10,30) as well as compared with the marathon and ultramarathon studies (11,15), where up to 200-fold (29) increases have been reported. Reasons for this lower than anticipated response are not entirely clear, yet, collectively, these data further support the role of exercise load (volume and intensity) in contributing to the magnitude of cytokine responses to exercise. Similar to IL-10, the resting IL-1ra concentrations were about 65% higher among healthy subjects at rest when compared with illness-prone subjects, even though the magnitudes of the postexercise responses were not markedly different between the groups. Given the powerful antiinflammatory actions of IL-1ra (17), the lower concentrations in the illness-prone group provide further evidence suggestive of a reduced capacity for antiinflammatory regulation among these athletes. Whether this effect is evident at higher workloads, where greater perturbations in IL-1ra would be expected, should be addressed in future investigations.

Alterations in immune system function are the most common explanation for the apparent increased risk for URS in elite athletes after exhaustive competitive events. Evidence from the current study of decreasing IL-12 concentrations after exercise lends support to the theory of exercise-induced disruptions in Th1 and Th2 balance, as contributing to a postexercise window period of increases susceptibility to viral illness (4,22). However, considering the low levels of detection, substantial intra- and interindividual variation, and lack of a clear impact on IL-2 and IL-4, by itself, this IL-12 finding is unlikely to account for the dichotomous illness patterns between the two groups in the current study. Instead, the classic pro- (IL-6 and IL-8) and antiinflammatory (IL-10, IL-1ra) cytokines seemed to be more useful in distinguishing between the healthy and illness-prone runners.

The current investigation provides a more relevant characterization of the impact of typical day-to-day training activities on immune system function than studies of marathon and ultramarathon events. The moderate RPE and heart rate values recorded for the exercise tests in this study were all considerably lower than would be expected during marathon and ultramarathon events. In addition, considering that the treadmill running was an accustomed activity for the majority of subjects, it is unlikely that any substantial muscle damage was incurred, thus eliminating a recognized trigger of postexercise elevations in cytokine concentrations (2,12,23). The exercise tests used in this study are more representative of short-easy, long-easy, and moderate-intensity interval training sessions undertaken by most recreational and highly trained athletes in individual and team sports. We observed recovery of inflammatory control within 10-24 h, indicating that workloads of 65% V˙O2max, mean HR of 75-80% of max, and a "somewhat hard' perception of effort, should pose only minimal risk to the inflammatory control mechanisms in otherwise healthy individuals. This information may also be useful for athletes recovering from illness or states of fatigue/overtraining, who need a graded return to full training without excessive loading of the immune system.

In summary, we observed a potential defect in antiinflammatory cytokine regulation among a group of illness-prone distance runners. In contrast, in the healthy runners, pro-and antiinflammatory responses to controlled exercise loads were regulated in a more proportionate manner. The responses of both groups were lower in magnitude than those described in other more strenuous settings of marathons and ultramarathons. The apparent defect in cytokine regulation described here may partly explain the history of frequent URS reported by the illness-prone athletes involved in this study. Profiling of cytokine concentrations at rest and in response to controlled doses of exercise may be beneficial in understanding the mechanisms contributing to an increased susceptibility to URS in some athletes. Shorter-duration, moderate-intensity exercise should be well tolerated by highly trained distance runners returning from illness, or states of overreaching, without substantially increasing the risk of impairing immunity and antiinflammatory regulation. The applicability of these findings for athletes involved in other sports requires further investigation.

The generous participation of the runners involved in this study is gratefully acknowledged. The authors also wish to acknowledge the statistical advice provided by Professor Will Hopkins (AUT University, New Zealand). This research was funded by the Australian Institute of Sport and University of Newcastle (Australia).

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